bims-traimu 2023-02-26 papers

Issue of 2023‒02‒26
five papers selected by
Yantong Wan
Southern Medical University

Nat Immunol. 2023 Feb 20.

Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs.

Tao Wang, Jinjing Zhang, Yanling Wang, Ying Li, Lu Wang, Yangle Yu, Yushi Yao.

Respiratory viral infections reprogram pulmonary macrophages with altered anti-infectious functions. However, the potential function of virus-trained macrophages in antitumor immunity in the lung, a preferential target of both primary and metastatic malignancies, is not well understood. Using mouse models of influenza and lung metastatic tumors, we show here that influenza trains respiratory mucosal-resident alveolar macrophages (AMs) to exert long-lasting and tissue-specific antitumor immunity. Trained AMs infiltrate tumor lesions and have enhanced phagocytic and tumor cell cytotoxic functions, which are associated with epigenetic, transcriptional and metabolic resistance to tumor-induced immune suppression. Generation of antitumor trained immunity in AMs is dependent on interferon-γ and natural killer cells. Notably, human AMs with trained immunity traits in non-small cell lung cancer tissue are associated with a favorable immune microenvironment. These data reveal a function for trained resident macrophages in pulmonary mucosal antitumor immune surveillance. Induction of trained immunity in tissue-resident macrophages might thereby be a potential antitumor strategy.

DOI: https://doi.org/10.1038/s41590-023-01428-x

Rheumatology (Oxford). 2023 Feb 20. pii: kead061. [Epub ahead of print]

Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production.

OBJECTIVE: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production.METHODS: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes.
RESULTS: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production.
CONCLUSIONS: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.

Keywords: IL-6; epigenetics; immunometabolism; monocyte/macrophage; trained immunity

DOI: https://doi.org/10.1093/rheumatology/kead061

Sci Rep. 2023 Feb 22. 13(1): 3107

Mycobacterium bovis BCG increase the selected determinants of monocyte/macrophage activity, which were diminished in response to gastric pathogen Helicobacter pylori.

Weronika Gonciarz, Maciej Chyb, Magdalena Chmiela.

High antibiotic resistance of gastric pathogen Helicobacter pylori (Hp) and the ability to escape the host immune response prompt searching for therapeutic immunomodulators. Bacillus Calmette-Guerin (BCG) vaccine with Mycobacterium bovis (Mb) is a candidate for modulation the activity of immunocompetent cells, and onco-BCG formulation was successfully used in immunotherapy of bladder cancer. We determined the influence of onco-BCG on the phagocytic capacity of human THP-1 monocyte/macrophage cells, using the model of Escherichia coli bioparticles and Hp fluorescently labeled. Deposition of cell integrins CD11b, CD11d, CD18, membrane/soluble lipopolysaccharide (LPS) receptors, CD14 and sCD14, respectively, and the production of macrophage chemotactic protein (MCP)-1 were determined. Furthermore, a global DNA methylation, was also assessed. Human THP-1 monocytes/macrophages (TIB 202) primed or primed and restimulated with onco-BCG or Hp, were used for assessment of phagocytosis towards E. coli or Hp, surface (immunostaining) or soluble activity determinants, and global DNA methylation (ELISA). THP-1 monocytes/macrophages primed/restimulated with BCG showed increased phagocytosis capacity towards E. coli fluorescent particles, elevated expression of CD11b, CD11d, CD18, CD14, sCD14, increased MCP-1 secretion and DNA methylation. Preliminary results indicate that BCG mycobacteria may also induce the phagocytosis of H. pylori by THP-1 monocytes. Priming or priming and restimulation of monocytes/macrophages with BCG resulted in an increased activity of these cells, which was negatively modulated by Hp.

DOI: https://doi.org/10.1038/s41598-023-30250-6

Front Immunol. 2023 ;14 1119879

Signaling events induced by lipopolysaccharide-activated Toll in response to bacterial infection in shrimp.

Sheng Wang, Haoyang Li, Qinyao Li, Bin Yin, Sedong Li, Jianguo He, Chaozheng Li.

Toll-like receptors (TLR) play a crucial role in the detection of microbial infections in vertebrates and invertebrates. Mammalian TLRs directly recognize a variety of structurally conserved microbial components. However, invertebrates such as Drosophila indirectly recognize microbial products by binding to the cytokine-like ligand Spätzle, which activates signaling cascades that are not completely understood. In this study, we investigated the signaling events triggered by Toll in response to lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, and Vibrio parahaemolyticus infection in the arthropod shrimp Litopenaeus vannamei. We found that five of the nine Tolls from L. vannamei bound to LPS and the RNAi of LvToll1, LvToll2, LvToll3, LvToll5, and LvToll9 weakened LvDorsal-L phosphorylation induced by V. parahaemolyticus. All nine Tolls combined with MyD88 via the TIR domain, thereby conferring signals to the tumor necrosis factor receptor-associated factor 6 (TRAF6)-transforming growth factor-β activated kinase 1 binding protein 2 (TAB2)-transforming growth factor-β activated kinase 1 (TAK1) complex. Further examination revealed that the LvTRAF6-LvTAB2-LvTAK1 complex contributes to Dorsal-L phosphorylation and nuclear translocation during V. parahaemolyticus infection. Overall, shrimp Toll1/2/3/5/9-TRAF6/TAB2/TAK1-Dorsal cascades protect the host from V. parahaemolyticus infection, which provides a better understanding of how the innate immune system recognizes and responds to bacterial infections in invertebrates.

Keywords: TAK1/TAB2/TRAF6 complex; Toll; Vibrio parahaemolyticus; dorsal; shrimp

DOI: https://doi.org/10.3389/fimmu.2023.1119879

J Biol Chem. 2023 Feb 17. pii: S0021-9258(23)00175-8. [Epub ahead of print] 103043

p38 MAPK and MKP-1 control the glycolytic program via the bifunctional glycolysis regulator PFKFB3 during sepsis.

Carli E Mager, Justin M Mormol, Evan D Shelton, Parker R Murphy, Bridget A Bowman, Timothy J Barley, Xiantao Wang, Sarah C Linn, Kevin Liu, Leif D Nelin, Markus Hafner, Yusen Liu.

Hyperlactatemia often occurs in critically ill patients during severe sepsis/septic shock and is a powerful predictor of mortality. Lactate is the end product of glycolysis. While hypoxia due to inadequate oxygen delivery may result in anaerobic glycolysis, sepsis also enhances glycolysis under hyperdynamic circulation with adequate oxygen delivery. However, the molecular mechanisms involved are not fully understood. Mitogen-activated protein kinase (MAPK)a families regulate many aspects of the immune response during microbial infections. MAPK phosphatase (MKP)-1 serves as a feedback control mechanism for p38 and JNK MAPK activities via dephosphorylation. Here, we found that mice deficient in Mkp-1 exhibited substantially enhanced expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3, a key enzyme that regulates glycolysis following systemic E. coli infection. Enhanced PFKFB3 expression was observed in a variety of tissues and cell types, including hepatocytes, macrophages, and epithelial cells. In bone marrow-derived macrophages (BMDM), Pfkfb3 was robustly induced by both E. coli and lipopolysaccharide (LPS), and Mkp-1 deficiency enhanced PFKFB3 expression with no effect on Pfkfb3 mRNA stability. PFKFB3 induction was correlated with lactate production in both WT and Mkp-1-/- BMDM following LPS stimulation. Furthermore, we determined that a PFKFB3 inhibitor markedly attenuated lactate production, highlighting the critical role of PFKFB3 in the glycolysis program. Finally, pharmacological inhibition of p38 MAPK, but not JNK, substantially attenuated PFKFB3 expression and lactate production. Taken together, our studies suggest a critical role of p38 MAPK and MKP-1 in the regulation of glycolysis during sepsis.

Keywords: Infection; c-Jun N-terminal kinase (JNK); dual-specificity phosphoprotein phosphatase; glycolysis; p38 MAPK; sepsis

DOI: https://doi.org/10.1016/j.jbc.2023.103043