bims-mampoc 2022-02-20 papers

bims-mampoc

Biomed News

on Macrophage metabolism and polarization in cancer

Issue of 2022‒02‒20
thirty papers selected by
Alessandra Castegna
University of Bari “Aldo Moro”

Tumor-Associated Macrophages: Reasons to Be Cheerful, Reasons to Be Fearful.
Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.
Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword.
Atractylenolide II inhibits tumor-associated macrophages (TAMs)-induced lung cancer cell metastasis.
Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections.
VSSP abrogates murine ovarian tumor-associated myeloid cell-driven immune suppression and induces M1 polarization in tumor-associated macrophages from ovarian cancer patients.
Tilting the Scales: Sirtuin 1 Favors Proinflammatory Macrophage Response Via Inflammasome Signaling and Metabolic Reprogramming.
Cassiaside C Inhibits M1 Polarization of Macrophages by Downregulating Glycolysis.
Inhibition of the VEGF signaling pathway attenuates tumor‑associated macrophage activity in liver cancer.
mTOR Signaling Components in Tumor Mechanobiology.
Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
Metabo-reciprocity in cell mechanics: feeling the demands/feeding the demand.
GBE1 Is an Independent Prognostic Marker and Associated With CD163+ Tumor-Associated Macrophage Infiltration in Lung Adenocarcinoma.
Differential expression of PD‑L1 and PD‑L2 is associated with the tumor microenvironment of TILs and M2 TAMs and tumor differentiation in non‑small cell lung cancer.
UCHL1 Promoted Polarization of M1 Macrophages by Regulating the PI3K/AKT Signaling Pathway.
Cytidine acetylation yields a hypoinflammatory synthetic messenger RNA.
Circadian Control of REDOX Reactions in the Macrophage Inflammatory Response.
Bone mesenchymal stem cell-derived extracellular vesicles inhibit DAPK1-mediated inflammation by delivering miR-191 to macrophages.
Protein Lipidation by Palmitate Controls Macrophage Function.
Combination of anti-PD-L1 antibody with peptide MEL-dKLA targeting M2 tumor-associated macrophages suppresses breast cancer metastasis.
Interactions between Radiation and One-Carbon Metabolism.
Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation.
Brain cancer cell-derived matrices and effects on astrocyte migration.
The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer.
Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.
Stable Isotope Tracing and Metabolomics to Study In Vivo Brown Adipose Tissue Metabolic Fluxes.
Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair.
PD-L1 near Infrared Photoimmunotherapy of Ovarian Cancer Model.
Macrophage polarization by potential nutraceutical compounds: A strategic approach to counteract inflammation in atherosclerosis.
Brucella induces M1 to M2 polarization of macrophages through STAT6 signaling pathway to promote bacterial intracellular survival.

Exp Suppl. 2022 ;113 107-140

Tumor-Associated Macrophages: Reasons to Be Cheerful, Reasons to Be Fearful.

Izabela Szulc-Kielbik, Michal Kielbik.

  Tumor microenvironment (TME) is a complex and constantly evolving entity that consists not only of cancer cells, but also of resident host cells and immune-infiltrating cells, among which macrophages are significant components, due to their diversity of functions through which they can influence the immune response against tumor cells. Macrophages present in tumor environment are termed as tumor-associated macrophages (TAMs). They are strongly plastic cells, and depending on the TME stimuli (i.e., cytokines, chemokines), TAMs polarize to antitumoral (M1-like TAMs) or protumoral (M2-like TAMs) phenotype. Both types of TAMs differ in the surface receptors' expression, activation of intracellular signaling pathways, and ability of production and various metabolites release. At the early stage of tumor formation, TAMs are M1-like phenotype, and they are able to eliminate tumor cells, i.e., by reactive oxygen species formation or by presentation of cancer antigens to other effector immune cells. However, during tumor progression, TAMs M2-like phenotype is dominating. They mainly contribute to angiogenesis, stromal remodeling, enhancement of tumor cells migration and invasion, and immunosuppression. This wide variety of TAMs' functions makes them an excellent subject for use in developing antitumor therapies which mainly is based on three strategies: TAMs' elimination, reprograming, or recruitment inhibition.

Keywords:  Angiogenesis; M1/M2 macrophages; Metastasis; Polarization; TAMs targeting therapies; Tumor cells; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/978-3-030-91311-3_4
Elife. 2022 02 14. pii: e73796. [Epub ahead of print]11

Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.

Seth Boyer, Ho-Joon Lee, Nina Steele, Li Zhang, Peter Sajjakulnukit, Anthony Andren, Matthew H Ward, Rima Singh, Venkatesha Basrur, Yaqing Zhang, Alexey I Nesvizhskii, Marina Pasca di Magliano, Christopher J Halbrook, Costas A Lyssiotis.

  The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEMs) in vitro and performed detailed, multiomic characterization (i.e., transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single-cell RNA sequencing dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.

Keywords:  cancer biology; human; immunology; inflammation; metabolomics; mouse; pancreatic cancer; proteomics; tumor-associated macrophages

DOI:  https://doi.org/10.7554/eLife.73796
Int J Mol Sci. 2022 Feb 04. pii: 1808. [Epub ahead of print]23(3):

Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword.

Sarah E Blitz, Ari D Kappel, Florian A Gessler, Neil V Klinger, Omar Arnaout, Yi Lu, Pier Paolo Peruzzi, Timothy R Smith, Ennio A Chiocca, Gregory K Friedman, Joshua D Bernstock.

  Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation-both immunostimulatory and immunosuppressant-and suggest future directions to maximize OV efficacy.

Keywords:  glioblastoma (GBM); oncolytic virotherapy; tumor microenvironment; tumor-associated macrophages/microglia (TAMs)

DOI:  https://doi.org/10.3390/ijms23031808
Immunopharmacol Immunotoxicol. 2022 Feb 15. 1-11

Atractylenolide II inhibits tumor-associated macrophages (TAMs)-induced lung cancer cell metastasis.

Yunting Zhang, Yuxi Liu, Jianguang Wang, Zongying Jiang, Lin Zhang, Yong Cui, Danyu Zhao, Yanjie Wang.

  OBJECTIVE: M2-like tumor-associated macrophages (TAMs) play a crucial role in promoting tumor proliferation, angiogenesis, and metastasis. In the current study, we investigated the relationship between macrophage polarization and the antitumor effect of Atractylenolide II (AT-II) in lung cancer cells.MATERIALS AND METHODS: Cell viability, migration, and invasion were determined by MTT assay, wound healing assay, and transwell assay, respectively. Flow cytometry analysis showed the percentage of CD206+ cells. Gene expression was determined by real-time PCR, western blotting, and immunofluorescence staining. Lewis lung carcinoma mouse xenograft and metastasis models were used to examine the effects of AT-II on lung cancer in vivo.
RESULTS: AT-II (2.5 and 5 µM) did not cause significant inhibition of A549 cell viability but markedly inhibited IL-4/IL-13-induced M2-like polarization, evidenced by the decreased expression of the M2 surface marker CD206, down-regulation of specific M2-marker genes (Arg-1, IL-10 and TGF-β) as well as inhibition of M2 macrophages-mediated invasion and migration of A549 cells. In addition, AT-II inhibited IL-4/IL-13-induced activation of the STAT6 signaling pathway that is vital in the M2-like polarization of macrophages. In animal models, administration of AT-II (50 mg kg-1, i.g., QD for 21 days) significantly inhibited tumor growth, reduced pulmonary metastatic nodules, and down-regulated the percentages of M2 macrophages (F4/80+ and CD206+) in total macrophages (F4/80+) in tumor tissues and pulmonary metastatic nodules.
CONCLUSIONS: AT-II effectively inhibits M2-like polarization, thereby inhibiting lung cancer cell metastasis both in vivo and in vitro, revealing a novel potential strategy for the antitumor effect of AT-II.

Keywords:  Atractylenolide II; M2-like polarization; STAT6 signaling pathway; lung cancer; tumor-associated macrophages

DOI:  https://doi.org/10.1080/08923973.2022.2037629
Front Immunol. 2022 ;13 780839

Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections.

Thierry Gauthier, Wanjun Chen.

  Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.

Keywords:  SARS – CoV – 2; immunometabolism; infections; macrophage; therapeutics

DOI:  https://doi.org/10.3389/fimmu.2022.780839
Cancer Immunol Immunother. 2022 Feb 15.

VSSP abrogates murine ovarian tumor-associated myeloid cell-driven immune suppression and induces M1 polarization in tumor-associated macrophages from ovarian cancer patients.

Anm Nazmul H Khan, Tiffany R Emmons, William J Magner, Emad Alqassim, Kelly L Singel, Jason Ricciuti, Kevin H Eng, Kunle Odunsi, Thomas B Tomasi, Kelvin Lee, Scott I Abrams, Circe Mesa, Brahm H Segal.

  The ovarian tumor microenvironment (TME) is characterized by the accumulation of immunosuppressive tumor-associated macrophages (TAMs) and granulocytic cells. Very small size particles (VSSP), comprised of the ganglioside NAcGM3 and Neisseria meningitidis derived outer membrane vesicles, is being developed as a nanoparticulated modulator of innate immunity. Prior studies have shown that VSSP enhanced antigen-specific cytotoxic T cell responses and reduced the suppressive phenotype of splenic granulocytic cells in tumor-bearing mice. Here, we hypothesized that intraperitoneal VSSP would modify myeloid cell accumulation and phenotypes in the ovarian TME and abrogate suppressor function of TAMs and tumor-associated granulocytic cells. In the ID8 syngeneic model of epithelial ovarian cancer, VSSP reduced peritoneal TAMs and induced M1-like polarization in TAMs. In addition, VSSP stimulated peritoneal inflammation characterized by increased granulocytes and monocytes, including inflammatory monocytic cells. VSSP treatment resulted in peritoneal TAMs and granulocytic cells being less suppressive of ex vivo stimulated CD8+ T cell responses. VSSP alone and combined with anti-PD-1 modestly but significantly prolonged survival in tumor-bearing mice. In addition, ex vivo treatment with VSSP induced M1-like polarization in TAMs from patients with metastatic ovarian cancer and variably abrogated their suppressor phenotype. VSSP treatment also partially abrogated the induction of suppressor function in healthy donor neutrophils exposed to ascites supernatants from patients with ovarian cancer. Together, these results point to VSSP reprogramming myeloid responses resulting in abrogation of suppressive pathways and raise the potential for administration of VSSP into the TME to enhance anti-tumor immunity.

Keywords:  Dicer; Epithelial ovarian cancer; Granulocytes; Immunomodulatory drug; Immunosuppression; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s00262-022-03156-x
Cell Mol Gastroenterol Hepatol. 2022 Feb 09. pii: S2352-345X(22)00011-X. [Epub ahead of print]

Tilting the Scales: Sirtuin 1 Favors Proinflammatory Macrophage Response Via Inflammasome Signaling and Metabolic Reprogramming.

Lindsey Kennedy.

DOI: https://doi.org/10.1016/j.jcmgh.2022.01.011
Int J Mol Sci. 2022 Feb 01. pii: 1696. [Epub ahead of print]23(3):

Cassiaside C Inhibits M1 Polarization of Macrophages by Downregulating Glycolysis.

Ye Jin Kim, Sungwoo Lee, Jonghwa Jin, Hyein Woo, Yeon-Kyung Choi, Keun-Gyu Park.

  Classically activated M1 macrophages reprogram their metabolism towards enhanced glycolysis to obtain energy and produce pro-inflammatory cytokines after activation by mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor (HIF)-1α. Thus, a strategy that constrains M1 polarization of macrophages via downregulation of glycolysis is essential for treating chronic inflammatory diseases. Cassiae semen has pharmacological activity against various inflammatory diseases. However, it is unclear whether specific compounds within Cassia seeds affect M1 polarization of macrophages. Here, we investigated whether Cassiaside C napthopyrone from Cassiae semen inhibits M1 polarization by downregulating glycolysis. We found that Cassiaside C reduced expression of inducible nitric oxide synthase and cyclooxygenase-2 and the phosphorylation of nuclear factor kappa B, all of which are upregulated in lipopolysaccharide (LPS)/interferon (IFN)-γ-treated Raw264.7 cells and peritoneal macrophages. Moreover, Cassiaside C-treated macrophages showed marked suppression of LPS/IFN-γ-induced HIF-1α, pyruvate dehydrogenase kinase 1, and lactate dehydrogenase A expression, along with downregulation of the phosphoinositide 3-kinases (PI3K)/AKT/mTORC1 signaling pathway. Consequently, Cassiaside C attenuated enhanced glycolysis and lactate production, but rescued diminished oxidative phosphorylation, in M1 polarized macrophages. Thus, Cassiaside C dampens M1 polarization of macrophages by downregulating glycolysis, which could be exploited as a therapeutic strategy for chronic inflammatory conditions.

Keywords:  Cassiaside C; M1 polarization; glycolysis; macrophage

DOI:  https://doi.org/10.3390/ijms23031696
Oncol Rep. 2022 Apr;pii: 71. [Epub ahead of print]47(4):

Inhibition of the VEGF signaling pathway attenuates tumor‑associated macrophage activity in liver cancer.

Shohei Okikawa, Yuji Morine, Yu Saito, Shinichiro Yamada, Kazunori Tokuda, Hiroki Teraoku, Katsuki Miyazaki, Shoko Yamashita, Tetsuya Ikemoto, Satoru Imura, Mitsuo Shimada.

  Tumor‑associated macrophage (TAMs) are paramount for tumor progression and immune tolerance in the tumor microenvironment of various types of cancer, including liver cancer. The aim of the present study was to investigate the effect of vascular endothelial growth factor (VEGF) inhibition on TAM polarization and function during their interactions with macrophages and liver cancer cells. TAMs were induced by culturing M0 macrophages with cancer cell‑conditioned medium. TAMs cultured with cancer cell‑conditioned medium and vascular endothelial growth factor (VEGF) inhibitor were defined as modified TAMs, and the expression levels of TAM‑associated markers and VEGF receptor 2 were evaluated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The effects of TAMs and modified TAMs on cancer cell proliferation and migration were investigated using conditioned medium. Programmed death‑ligand 1 (PD‑L1) mRNA expression in modified TAMs and cancer cells cultured in modified TAM‑conditioned medium (TAM‑CM) for 48 h was examined using RT‑qPCR. In order to investigate signaling pathways in macrophages, western blot analysis was performed. CD163 and CD206 and M2 macrophage marker expression was upregulated in TAMs and modified TAMs. Modified TAM‑CM exhibited a decreased ability to promote cancer cell proliferation and migration in comparison with the use of TAM‑CM. The VEGF concentration was significantly higher in the TAMs than in M0 macrophages; however, the modified TAMs displayed a significantly lower VEGF secretion than TAMs. PD‑L1 expression was decreased in modified TAMs as compared with TAMs. Western blot analysis revealed that the Akt/mTOR signaling pathway was significantly suppressed in the modified TAMs compared with TAMs. It was observed that TAMs cultured in a VEGF‑depleted environment displayed lower secretion levels of cytokines involved in tumor progression and a decreased immune tolerance‑inducing ability. On the whole, the results of the present study suggested that VEGF inhibition in TAMs may be a potential therapeutic target for liver cancer.

Keywords:  PD‑L1; VEGF; liver cancer; tumor microenvironment; tumor‑associated macrophages

DOI:  https://doi.org/10.3892/or.2022.8282
Int J Mol Sci. 2022 Feb 05. pii: 1825. [Epub ahead of print]23(3):

mTOR Signaling Components in Tumor Mechanobiology.

Antonios N Gargalionis, Kostas A Papavassiliou, Efthimia K Basdra, Athanasios G Papavassiliou.

  Mechanistic target of rapamycin (mTOR) is a central signaling hub that integrates networks of nutrient availability, cellular metabolism, and autophagy in eukaryotic cells. mTOR kinase, along with its upstream regulators and downstream substrates, is upregulated in most human malignancies. At the same time, mechanical forces from the tumor microenvironment and mechanotransduction promote cancer cells' proliferation, motility, and invasion. mTOR signaling pathway has been recently found on the crossroads of mechanoresponsive-induced signaling cascades to regulate cell growth, invasion, and metastasis in cancer cells. In this review, we examine the emerging association of mTOR signaling components with certain protein tools of tumor mechanobiology. Thereby, we highlight novel mechanisms of mechanotransduction, which regulate tumor progression and invasion, as well as mechanisms related to the therapeutic efficacy of antitumor drugs.

Keywords:  Akt; PI3K; extracellular matrix; integrin; mTOR; matrix stiffness; mechanotransduction; tumor mechanobiology

DOI:  https://doi.org/10.3390/ijms23031825
Cancers (Basel). 2022 Jan 22. pii: 553. [Epub ahead of print]14(3):

Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.

Anna Halama, Karsten Suhre.

  Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.

Keywords:  cancer; cancer treatment; drug resistance; glutamine metabolism; glutaminolysis inhibition; metabolism

DOI:  https://doi.org/10.3390/cancers14030553
Trends Cell Biol. 2022 Feb 14. pii: S0962-8924(22)00028-9. [Epub ahead of print]

Metabo-reciprocity in cell mechanics: feeling the demands/feeding the demand.

Stéphanie Torrino, Thomas Bertero.

  Altered metabolic programs and corruption of tissue architecture are hallmarks of disease. The spatiotemporal control of cell behavior requires transmission of information from the complex structure of tissues to their constituent cells. Cytoskeletal mechanotransduction enables this transmission by sensing mechanical environments and adapting cellular behaviors. However, this process requires energy. Recent findings have shed light on the bidirectional relationship between mechanical forces and upstream and downstream metabolic cues. We discuss recent advances in the reciprocal regulation ('metabo-reciprocity') that allows cells to adapt their metabolic needs to their mechanically constrained environment but can also contribute to adjustable feedback that promotes disease progression.

Keywords:  amino acid metabolism; cell mechanics; glucose metabolism; lipid metabolism; mechanotransduction

DOI:  https://doi.org/10.1016/j.tcb.2022.01.013
Front Oncol. 2021 ;11 781344

GBE1 Is an Independent Prognostic Marker and Associated With CD163+ Tumor-Associated Macrophage Infiltration in Lung Adenocarcinoma.

Yicheng Liang, Yangyang Lei, Mei Liang, Minjun Du, Zixu Liu, Xingkai Li, Xiangzhi Meng, Boxuan Zhou, Yushun Gao.

  Glycogen branching enzyme (GBE1) is a critical gene that participates in regulating glycogen metabolism. However, the correlations between GBE1 expression and the prognosis and tumor-associated macrophages in lung adenocarcinoma (LUAD) also remain unclear. Herein, we firstly analyzed the expression level of GBE1 in LUAD tissues and adjacent lung tissues via The Cancer Genome Atlas (TCGA) database. The effect of GBE1 on prognosis was estimated by utilizing TCGA database and the PrognoScan database. The relationships between the clinical characteristics and GBE1 expression were evaluated via TCGA database. We then investigated the relationships between GBE1 and infiltration of immune cells in LUAD by utilizing the CIBERSORT algorithm and Tumor Immune Estimation Resource (TIMER) database. In addition, we used a tissue microarray (TMA) containing 92 LUAD tissues and 88 adjacent lung tissues with immunohistochemistry staining to verify the association between GBE1 expression and clinical characteristics, as well as the immune cell infiltrations. We found the expression level of GBE1 was significantly higher in LUAD tissues. High expression of GBE1 was associated with poorer overall survival (OS) in LUAD. In addition, high expression of GBE1 was correlated with advanced T classification, N classification, M classification, TNM stage, and lower grade. Moreover, GBE1 was positively correlated with infiltrating levels of CD163+ tumor-associated macrophages in LUAD. In conclusion, the expression of GBE1 is associated with the prognosis and CD163+ tumor-associated macrophage infiltration in LUAD, suggesting that it has potential to be prognostic and immunological biomarkers in LUAD.

Keywords:  CD163+ tumor-associated macrophage infiltration; GBE1; LUAD; clinical characteristics; immunohistochemistry (IHC); prognosis; tissue microarray (TMA)

DOI:  https://doi.org/10.3389/fonc.2021.781344
Oncol Rep. 2022 Apr;pii: 73. [Epub ahead of print]47(4):

Differential expression of PD‑L1 and PD‑L2 is associated with the tumor microenvironment of TILs and M2 TAMs and tumor differentiation in non‑small cell lung cancer.

Ryota Sumitomo, Cheng-Long Huang, Masaaki Fujita, Hiroyuki Cho, Hiroshi Date.

  To improve the treatment strategy of immune‑checkpoint inhibitors for non‑small cell lung cancer (NSCLC), a comprehensive analysis of programmed death‑ligand (PD‑L)1 and PD‑L2 expression is clinically important. The expression of PD‑L1 and PD‑L2 on both tumor cells (TCs) and tumor‑infiltrating immune cells (ICs) was investigated, with respect to tumor‑infiltrating lymphocytes (TILs) and M2 tumor‑associated macrophages (TAMs), which are key components of the tumor microenvironment, in 175 patients with resected NSCLC. The TIL and M2 TAM densities were associated with the expression of PD‑L1 on the two TCs (both P<0.0001) and ICs (both P<0.0001). The TIL and M2 TAM densities were also associated with the expression of PD‑L2 on both TCs (P=0.0494 and P=0.0452, respectively) and ICs (P=0.0048 and P=0.0125, respectively). However, there was no correlation between the percentage of PD‑L1‑positive TCs and the percentage of PD‑L2‑positive TCs (r=0.019; P=0.8049). Meanwhile, tumor differentiation was significantly associated with the PD‑L1 expression on TCs and ICs (P=0.0002 and P<0.0001, respectively). By contrast, tumor differentiation was inversely associated with the PD‑L2 expression on both TCs and ICs (P=0.0260 and P=0.0326, respectively). In conclusion, the combined evaluation of PD‑L1 and PD‑L2 expression could be clinically important in the treatment strategy of immune‑checkpoint inhibitors in patients with NSCLC. In particular, the evaluation of PD‑L2 expression may be necessary for patients with PD‑L1‑negative NSCLC.

Keywords:  differentiation; immune cell; lung cancer; lymphocyte; macrophage; programmed death‑ligand 1/2; tumor cell; tumor microenvironment

DOI:  https://doi.org/10.3892/or.2022.8284
J Inflamm Res. 2022 ;15 735-746

UCHL1 Promoted Polarization of M1 Macrophages by Regulating the PI3K/AKT Signaling Pathway.

Yulan Huang, Shitong He, Yitian Chen, Junli Sheng, Yuling Fu, Xialin Du, Yalong Yang, Honglin Liu, Zhenyu Han, Yingqi Huang, Qian Wen, Chaoying Zhou, Xinying Zhou, Shengfeng Hu, Li Ma.

  Background: As deubiquitinases (DUBs), ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to play a crucial role in regulating diverse biological processes. However, its function in macrophage polarization remains unclear.Methods: We performed in vivo and in vitro experiments to investigate the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a kind of DUBs, in macrophage differentiation by using UCHL1-deficiency mice.
Results: We demonstrated that LPS stimulation induced UCHL1 expression in macrophages. The deficiency of UCHL1 expression decreased the expression of CD80 and CD86 but increased the expression of CD206. The expression of TNF-α, IL-6, iNOS, and IL-10 was downregulated, while that of Arg1, Ym1, and Fizz1 was upregulated in UCHL1 deficient macrophages. Moreover, we observed that UCHL1 promoted the degradation of p110α through autophagy, but paradoxically increased the activity of AKT, thereby promoting polarization of macrophages into pro-inflammatory states.
Conclusion: In this study, we identified UCHL1 as a positive regulator of M1 macrophage polarization. Our findings may help in developing therapeutic interventions for the treatment of inflammatory diseases and pathogenic infections.

Keywords:  AKT; UCHL1; autophagy; macrophages; p110α

DOI:  https://doi.org/10.2147/JIR.S343487
Cell Chem Biol. 2022 Feb 17. pii: S2451-9456(21)00313-5. [Epub ahead of print]29(2): 312-320.e7

Cytidine acetylation yields a hypoinflammatory synthetic messenger RNA.

Kellie D Nance, Supuni Thalalla Gamage, Md Masud Alam, Acong Yang, Michaella J Levy, Courtney N Link, Laurence Florens, Michael P Washburn, Shuo Gu, Joost J Oppenheim, Jordan L Meier.

  Synthetic messenger RNA (mRNA) is an emerging therapeutic platform with important applications in oncology and infectious disease. Effective mRNA medicines must be translated by the ribosome but not trigger a strong nucleic acid-mediated immune response. To expand the medicinal chemistry toolbox for these agents, here we report the properties of the naturally occurring nucleobase N4-acetylcytidine (ac4C) in synthetic mRNAs. We find that ac4C is compatible with, but does not enhance, protein production in the context of synthetic mRNA reporters. However, replacement of cytidine with ac4C diminishes inflammatory gene expression in immune cells caused by synthetic mRNAs. Chemoproteomic capture indicates that ac4C alters the protein interactome of synthetic mRNAs, reducing binding to cytidine-binding proteins and an immune sensor. Overall, our studies illustrate the unique ability of ac4C to modulate RNA-protein interactions and provide a foundation for using N4-cytidine acylation to fine-tune the properties of nucleic acid therapeutics.

Keywords:  RNA modifications; acetylation; acetylcytidine; mRNA vaccines; messenger RNA; pseudouridine

DOI:  https://doi.org/10.1016/j.chembiol.2021.07.003
Antioxid Redox Signal. 2022 Feb 15.

Circadian Control of REDOX Reactions in the Macrophage Inflammatory Response.

James Rian O'Siorain, Annie Curtis.

SIGNIFICANCE: Macrophages are immune sentinels located throughout the body that function in both the amplification and resolution of the inflammatory response. The circadian clock has emerged as a central regulator of macrophage inflammation. Reduction-oxidation (REDOX) reactions are central to both circadian clock and macrophage function. Recent Advances: Circadian regulation of metabolism controls the macrophage inflammatory response, whereby disruption of the clock causes dysfunctional inflammation. Altering metabolism and reactive oxygen/nitrogen species (RONS) production rescues the inflammatory phenotype of clock-disrupted macrophages.CRITICAL ISSUES: The circadian clock possesses many layers of regulation. Understanding how REDOX reactions coordinate clock function is critical to uncover the full extent of circadian regulation of macrophage inflammation. We provide insights into how circadian regulation of REDOX affects macrophage pattern recognition receptor signaling, immunometabolism, phagocytosis, and inflammasome activation.
FUTURE DIRECTIONS: Many diseases associated with aberrant macrophage derived inflammation exhibit time of day rhythms in disease symptoms and severity and are sensitive to circadian disruption. Macrophage function is highly dependent on REDOX reactions that signal through RONS. Future studies are needed to evaluate the extent of circadian control of macrophage inflammation, specifically in the context of REDOX signaling.

DOI: https://doi.org/10.1089/ars.2022.0014
Biochem Biophys Res Commun. 2022 Feb 05. pii: S0006-291X(22)00185-1. [Epub ahead of print]598 32-39

Bone mesenchymal stem cell-derived extracellular vesicles inhibit DAPK1-mediated inflammation by delivering miR-191 to macrophages.

Hui Liu, Luming Zhang, Meilian Li, Fengzhi Zhao, Fan Lu, Feng Zhang, Sida Chen, Juntao Guo, Rui Zhang, Hanyan Yin.

  Alveolar macrophage activation and apoptosis are vital contributors to sepsis-associated acute lung injury (ALI). However, the mechanisms of alveolar macrophage activation are yet to be clarified. Death-associated protein kinase 1 (DAPK1) is one of the potential candidates that play crucial roles in regulating alveolar macrophage inflammation. Herein, we found that primary human bone mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) antagonize LPS-induced inflammation in the THP-1 human macrophage-like cell line. Mechanistically, LPS stimulation elevates the expression of DAPK1 and the inflammation markers in THP-1 cells, while BMSC-derived EVs inhibit the expression of DAPK1 and inflammation through delivering miR-191, which can target the 3'-UTR of the DAPK1 mRNA and therefore suppress its translation. The importance of DAPK1 in the activation of THP-1 is also stressed in this study. Our findings provide evidence that BMSC-derived EVs regulate the alveolar macrophage inflammation and highlight BMSC-derived EVs as a potential vehicle to deliver biomacromolecules to macrophages.

Keywords:  Bone mesenchymal stem cell; DAPK1; Extracellular vesicles; Inflammation factors; THP-1 macrophages; miR-191

DOI:  https://doi.org/10.1016/j.bbrc.2022.02.009
Cells. 2022 Feb 06. pii: 565. [Epub ahead of print]11(3):

Protein Lipidation by Palmitate Controls Macrophage Function.

Jeroen Guns, Sam Vanherle, Jerome J A Hendriks, Jeroen F J Bogie.

  Macrophages are present in all tissues within our body, where they promote tissue homeostasis by responding to microenvironmental triggers, not only through clearance of pathogens and apoptotic cells but also via trophic, regulatory, and repair functions. To accomplish these divergent functions, tremendous dynamic fine-tuning of their physiology is needed. Emerging evidence indicates that S-palmitoylation, a reversible post-translational modification that involves the linkage of the saturated fatty acid palmitate to protein cysteine residues, directs many aspects of macrophage physiology in health and disease. By controlling protein activity, stability, trafficking, and protein-protein interactions, studies identified a key role of S-palmitoylation in endocytosis, inflammatory signaling, chemotaxis, and lysosomal function. Here, we provide an in-depth overview of the impact of S-palmitoylation on these cellular processes in macrophages in health and disease. Findings discussed in this review highlight the therapeutic potential of modulators of S-palmitoylation in immunopathologies, ranging from infectious and chronic inflammatory disorders to metabolic conditions.

Keywords:  S-palmitoylation; inflammation; innate immunity; macrophages; protein acetylation

DOI:  https://doi.org/10.3390/cells11030565
Cancer Commun (Lond). 2022 Feb 16.

Combination of anti-PD-L1 antibody with peptide MEL-dKLA targeting M2 tumor-associated macrophages suppresses breast cancer metastasis.

Chanju Lee, Hyunji Lee, Hayoon Cho, Soyoung Kim, Ilseob Choi, Young-Sik Hwang, Hyunju Jeong, Hogi Jang, Sehyun Pak, Deok-Sang Hwang, Ik-Hwan Han, Hyunsu Bae.

DOI: https://doi.org/10.1002/cac2.12276
Int J Mol Sci. 2022 Feb 08. pii: 1919. [Epub ahead of print]23(3):

Interactions between Radiation and One-Carbon Metabolism.

Navyateja Korimerla, Daniel R Wahl.

  Metabolic reprogramming is a hallmark of cancer. Cancer cells rewire one-carbon metabolism, a central metabolic pathway, to turn nutritional inputs into essential biomolecules required for cancer cell growth and maintenance. Radiation therapy, a common cancer therapy, also interacts and alters one-carbon metabolism. This review discusses the interactions between radiation therapy, one-carbon metabolism and its component metabolic pathways.

Keywords:  cancer therapy; folate cycle; methionine cycle; one-carbon metabolism; radiation therapy

DOI:  https://doi.org/10.3390/ijms23031919
Cell Rep. 2022 02 15. pii: S2211-1247(22)00112-7. [Epub ahead of print]38(7): 110391

Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation.

Yi Li, Yu-Chen Li, Xiao-Tian Liu, Lu Zhang, Yi-Hua Chen, Qiong Zhao, Wen Gao, Baolin Liu, Hua Yang, Ping Li.

  The metabolism of activated macrophages relies on aerobic glycolysis, while mitochondrial oxidation is disrupted. In lipopolysaccharide-activated macrophages, the citrate carrier (CIC) exports citrate from mitochondria to enhance glycolytic genes through histone acetylation. CIC inhibition or Slc25a1 knockdown reduces the occupancy of H3K9ac to hypoxia-inducible factor-1α (HIF-1α) binding sites in promoters of glycolytic genes to restrain glycolysis. HIF-1α also transcriptionally upregulates immune-responsive gene 1 for itaconate production, which is inhibited by CIC blocking. Isotopic tracing of [U-13C6] glucose shows that CIC blockage prevents citrate accumulation and itaconate production by reducing glycolytic flux and facilitating metabolic flux in the TCA cycle. Isotopic tracing of [U-13C5] glutamine reveals that CIC inhibition reduces succinate accumulation from glutaminolysis and the gamma-aminobutyric acid shunt by enhancing mitochondrial oxidation. By restraining glycolysis, CIC inhibition increases NAD+ content to ensure mitochondrial biogenesis for oxidative phosphorylation. Furthermore, blockage of citrate export reduces cerebral thrombosis by inactivation of peripheral macrophages.

Keywords:  HIF-1α; Irg1; citrate carrier; itaconate; succinate

DOI:  https://doi.org/10.1016/j.celrep.2022.110391
Cells Tissues Organs. 2022 Feb 15.

Brain cancer cell-derived matrices and effects on astrocyte migration.

Rebecca Louisthelmy, Brycen M Burke, R Chase Cornelison.

Cell-derived matrices are useful tools for studying the extracellular matrix (ECM) of different cell types and testing the effects on cell migration or wound repair. These matrices typically are generated using extended culture with ascorbic acid to boost ECM production. Applying this technique to cancer cell cultures could advance the study of cancer ECM and its effects on recruitment and training of the tumor microenvironment, but ascorbic acid is potently cytotoxic to cancer cells. Macromolecular crowding agents can also be added to increase matrix deposition based on the excluded volume principle. We report the use of macromolecular crowding (MMC) alone as an effective strategy to generate brain cancer cell-derived matrices for downstream analyses and cell migration studies. We cultured the mouse glioblastoma cell line GL261 for 1 week in the presence of three previously-reported MMC agents (carrageenan, Ficoll 70/400, and hyaluronic acid). We measured the resulting deposition of collagens and sulfated glycosaminoglycans using quantitative assays, as well as other matrix components by immunostaining. Both carrageenan and Ficoll promoted significantly more accumulation of total collagen content, sulfated glycosaminoglycan content, and fibronectin staining. Only Ficoll, however, also demonstrated a significant increase in collagen I staining. The results were more variable in 3D spheroid culture. We focused on Ficoll MMC matrices, which were isolated using the small molecule Raptinal to induce cancer cell apoptosis and matrix decellularization. The cancer cell-derived matrix promoted significantly faster migration of human astrocytes in a scratch wound assay, which may be explained by focal adhesion morphology and an increase in cellular metabolic activity. Ultimately, these data show MMC culture is a useful technique to generate cancer cell-derived matrices and study the effects on stromal cell migration related to wound repair.

DOI: https://doi.org/10.1159/000522609
Int J Mol Sci. 2022 Jan 25. pii: 1320. [Epub ahead of print]23(3):

The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer.

Meiyu Cheng, Huimei Yu, Qinghuan Kong, Bingrong Wang, Luyan Shen, Delu Dong, Liankun Sun.

  Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer.

Keywords:  DELE1; OMA1; endoplasmic reticulum stress; mitochondrial membranes; ovarian cancer

DOI:  https://doi.org/10.3390/ijms23031320
Commun Biol. 2022 Feb 15. 5(1): 132

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Idit Dotan, Jiaqi Yang, Jiro Ikeda, Ziv Roth, Evan Pollock-Tahiri, Harsh Desai, Tharini Sivasubramaniyam, Sonia Rehal, Josh Rapps, Yu Zhe Li, Helen Le, Gedaliah Farber, Edouard Alchami, Changting Xiao, Saraf Karim, Marcela Gronda, Michael F Saikali, Amit Tirosh, Kay-Uwe Wagner, Jacques Genest, Aaron D Schimmer, Vikas Gupta, Mark D Minden, Carolyn L Cummins, Gary F Lewis, Clinton Robbins, Jenny Jongstra-Bilen, Myron Cybulsky, Minna Woo.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

DOI: https://doi.org/10.1038/s42003-022-03078-5
Methods Mol Biol. 2022 ;2448 119-130

Stable Isotope Tracing and Metabolomics to Study In Vivo Brown Adipose Tissue Metabolic Fluxes.

Su Myung Jung, Johnny Le, Will G Doxsey, John A Haley, Grace Park, David A Guertin, Cholsoon Jang.

  Brown adipose tissue (BAT) demonstrates extraordinary metabolic capacity. Previous research using conventional radio tracers reveals that BAT can act as a sink for a diverse menu of nutrients; still, the question of how BAT utilizes these nutrients remains unclear. Recent advances in mass spectrometry (MS) coupled to stable isotope tracing methods have greatly improved our understanding of metabolism in biology. Here, we have developed a BAT-tailored metabolomics and stable isotope tracing protocol using, as an example, the universally labeled 13C-glucose, a key nutrient heavily utilized by BAT. This method enables metabolic roadmaps to be drawn and pathway fluxes to be inferred for each nutrient tracer within BAT and its application could uncover new metabolic pathways not previously appreciated for BAT physiology.

Keywords:  Brown adipose tissue; Brown fat; Gavage; Glucose; Liquid chromatography-mass spectrometry (LC-MS); Metabolism; Metabolomics; Stable isotope tracing; Temperature acclimation

DOI:  https://doi.org/10.1007/978-1-0716-2087-8_8
Exp Cell Res. 2022 Feb 12. pii: S0014-4827(22)00057-X. [Epub ahead of print] 113064

Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair.

Xinyun Han, Junxian Hu, Wenbo Zhao, Hongwei Lu, Jingjin Dai, Qingyi He.

  Angiogenesis is essential for successful bone defect repair. In normal tissue repair, the physiological inflammatory response is the main regulator of angiogenesis through the activity of macrophages and the cytokines secreted by them. In particular, M2 macrophages which secrete high levels of PDGF-BB are typically considered to promote angiogenesis. A hexapeptide [WKYMVm, (Trp-Lys-Tyr-Met-Val-D-Met-NH2)] has been reported to modulate inflammatory activities. However, the underlying mechanisms by which WKYMVm regulates macrophages remain unclear. In this study, the possible involvement by which WKYMVm induces the polarization of macrophages and affects their behaviors was evaluated. In vitro results showed that macrophages were induced to an M2 rather than M1 phenotype and the M2 phenotype was enhanced by WKYMVm through activation of the JAK1/STAT6 signaling pathway. It was also found that WKYMVm played an important role in the PDGF-BB production increase and proangiogenic abilities in M2 macrophages. Consistent with the results in vitro, the elevated M2/M0 ratio induced by WKYMVm enhanced the formation of new blood vessels in a femoral defect mouse model. These findings suggest that WKYMVm could be a promising alternative strategy for angiogenesis in bone repair by inducing M2 macrophage polarization.

Keywords:  Angiogenesis; Bone defect repair; M2 macrophage; WKYMVm peptide

DOI:  https://doi.org/10.1016/j.yexcr.2022.113064
Cancers (Basel). 2022 Jan 26. pii: 619. [Epub ahead of print]14(3):

PD-L1 near Infrared Photoimmunotherapy of Ovarian Cancer Model.

Jiefu Jin, Ishwarya Sivakumar, Yelena Mironchik, Balaji Krishnamachary, Flonné Wildes, James D Barnett, Chien-Fu Hung, Sridhar Nimmagadda, Hisataka Kobayashi, Zaver M Bhujwalla, Marie-France Penet.

  (1) Background: Despite advances in surgical approaches and drug development, ovarian cancer is still a leading cause of death from gynecological malignancies. Patients diagnosed with late-stage disease are treated with aggressive surgical resection and chemotherapy, but recurrence with resistant disease is often observed following treatment. There is a critical need for effective therapy for late-stage ovarian cancer. Photoimmunotherapy (PIT), using an antibody conjugated to a near infrared (NIR) dye, constitutes an effective theranostic strategy to detect and selectively eliminate targeted cell populations. (2) Methods: Here, we are targeting program death ligand 1 (PD-L1) using NIR-PIT in a syngeneic mouse model of ovarian cancer. PD-L1 PIT-mediated cytotoxicity was quantified in RAW264.7 macrophages and ID8-Defb29-VEGF cells in culture, and in vivo with orthotopic ID8-Defb29-VEGF tumors. (3) Results: Treatment efficacy was observed both in vitro and in vivo. (4) Conclusions: Our data highlight the need for further investigations to assess the potential of using NIR-PIT for ovarian cancer therapy to improve the treatment outcome of ovarian cancer.

Keywords:  ovarian cancer; photoimmunotherapy; theranostics

DOI:  https://doi.org/10.3390/cancers14030619
Free Radic Biol Med. 2022 Feb 11. pii: S0891-5849(22)00063-6. [Epub ahead of print]

Macrophage polarization by potential nutraceutical compounds: A strategic approach to counteract inflammation in atherosclerosis.

Barbara Sottero, Gabriella Testa, Paola Gamba, Erica Staurenghi, Serena Giannelli, Gabriella Leonarduzzi.

  Chronic inflammation represents a main event in the onset and progression of atherosclerosis and is closely associated with oxidative stress in a sort of vicious circle that amplifies and sustains all stages of the disease. Key players of atherosclerosis are monocytes/macrophages. According to their pro- or anti-inflammatory phenotype and biological function, lesional macrophages can release various mediators and enzymes, which in turn contribute to plaque progression and destabilization or, alternatively, lead to its resolution. Among the factors connected to atherosclerotic disease, lipid species carried by low density lipoproteins and pro-oxidant stimuli strongly promote inflammatory events in the vasculature, also by modulating the macrophage phenotyping. Therapies specifically aimed to balance macrophage inflammatory state are increasingly considered as powerful tools to counteract plaque formation and destabilization. In this connection, several molecules of natural origin have been recognized to be active mediators of diverse metabolic and signaling pathways regulating lipid homeostasis, redox state, and inflammation; they are, thus, considered as promising candidates to modulate macrophage responsiveness to pro-atherogenic stimuli. The current knowledge of the capability of nutriceuticals to target macrophage polarization and to counteract atherosclerotic lesion progression, based mainly on in vitro investigation, is summarized in the present review.

Keywords:  Atherosclerosis; Inflammation; Lipid homeostasis; Macrophage polarization; Nutraceuticals; Oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.010
Res Vet Sci. 2022 Feb 07. pii: S0034-5288(22)00044-3. [Epub ahead of print]145 91-101

Brucella induces M1 to M2 polarization of macrophages through STAT6 signaling pathway to promote bacterial intracellular survival.

Yueli Wang, Jing Xi, Jihai Yi, Chuang Meng, Xiaoli Zhao, Zhihua Sun, Huan Zhang, Xiaoyu Deng, Zhongchen Ma, Honghuan Li, Yong Wang, Chuangfu Chen.

  Brucella are serious intracellular pathogens that parasitize macrophages and cause persistent infection in humans and animals. Although macrophages are an important bridge between natural and acquired immunity, their role in Brucella infection is not completely clear. Recently, studies have reported that Brucella can induce macrophage polarization, although the specific molecular mechanism involved is not known. Therefore, in the current study the replication ability of Brucella melitensis strain M5 (Brucella M5) was examined as well as its macrophage polarization and cytokine production, in a host. The role of Signal transducers and activators of transcription 6 (STAT6) in macrophage polarization induced by Brucella infection was also investigated. The results showed that Brucella M5 survived in vivo for a prolonged period of time and caused damage to the spleen and uterus tissues. The expression of type M2 cytokines was induced after Brucella M5 infection. Immunohistochemistry showed that STAT6 was upregulated in spleen and uterus tissues. At the cellular level, Brucella M5 induced macrophagetransformation from M1 to M2-type during the later stage of infection. When STAT6 was silenced, the polarization of M2-type was inhibited, and the intracellular survival rate of Brucella decreased significantly. In conclusion, these findings demonstrate that STAT6 is the key factor regulates M2 polarization of macrophages and promotes the intracellular survival of Brucella in the late stage of infection and provides an explanation of the mechanism responsible for persistent Brucella infection.

Keywords:  Brucella; Macrophage polarization; Persistent infection; STAT6 signal pathway; Survival

DOI:  https://doi.org/10.1016/j.rvsc.2022.02.006