bims-stacyt 2023-12-31 papers

Cell Rep Med. 2023 Dec 21. pii: S2666-3791(23)00565-7. [Epub ahead of print] 101348

Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M.

Lucile Dollet, Leonidas S Lundell, Alexander V Chibalin, Logan A Pendergrast, Nicolas J Pillon, Elizabeth L Lansbury, Merve Elmastas, Scott Frendo-Cumbo, Jutta Jalkanen, Thais de Castro Barbosa, Daniel T Cervone, Kenneth Caidahl, Oksana Dmytriyeva, Atul S Deshmukh, Romain Barrès, Mikael Rydén, Harriet Wallberg-Henriksson, Juleen R Zierath, Anna Krook.

The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise. In cultured human adipocytes, oncostatin-M enhances MAPK signaling and regulates lipolysis. Oncostatin-M expression arises predominantly from adipose tissue immune cell fractions, while the corresponding receptors are expressed in adipocytes. Oncostatin-M expression increases in cultured human Thp1 macrophages following exercise-like stimuli. Our results suggest that immune cells, via secreted factors such as oncostatin-M, mediate a crosstalk between skeletal muscle and adipose tissue during exercise to regulate adipocyte metabolism and adaptation.

Keywords: adipose tissue; crosstalk; exercise; human; immune cells; inflammation; oncostatin-M; skeletal muscle; type 2 diabetes

DOI: https://doi.org/10.1016/j.xcrm.2023.101348

Front Immunol. 2023 ;14 1270774

Correlation of endoplasmic reticulum stress patterns with the immune microenvironment in hepatocellular carcinoma: a prognostic signature analysis.

Ke Zhan, Xin Yang, Shuang Li, Yang Bai.

Backgrounds: The extended duration of endoplasmic reticulum stress (ERS) can impact the progression of hepatocellular carcinoma (HCC) and the efficacy of immunotherapies by interacting with immune cells that have infiltrated the tumor microenvironment (TME).Methods and results: The study utilized a training cohort of 364 HCC patients with complete information from The Cancer Genome Atlas Program (TCGA) database, and a validation cohort of 231 HCC patients from the International Cancer Genome Consortium (ICGC) database. The genes related to ERS exhibiting a strong correlation with overall survival (OS) were identified using univariate Cox regression analysis. A 13-gene predictive signature was then produced through the least absolute shrinkage and selection operator (LASSO) regression approach. The data revealed that the ERS-associated gene signature effectively stratified patients into high- or low-risk groups regarding OS in both the training and validation cohorts (P < 0.0001 and P = 0.00029, respectively). Using the multivariate method, it is still an independent prognostic factor in both the training and validation cohorts (P < 0.001 and P = 0.008, respectively). Moreover, several metabolic pathways were identified to be enriched among the 13 genes in the predictive signature. When the ERS-associated gene signature was combined with the tumor-node-metastasis (TNM) stage, the ERS nomogram performed better than either the gene signature or the TNM stage alone (C-index values: 0.731, 0.729, and 0.573, respectively). Further analysis revealed that patients in the high-risk group exhibited increased infiltration of immune cells. Additionally, GP6 was downregulated in HCC tissues among these signature genes (P < 0.05), which was related to poor OS.
Conclusions: The data suggest that this novel ERS-associated gene signature could contribute to personalized cancer management for HCC. Moreover, targeting GP6 inhibition might be a potential method for HCC therapy.

Keywords: endoplasmic reticulum stress; gp6; hepatocellular carcinoma; immune microenvironment; prognosis

DOI: https://doi.org/10.3389/fimmu.2023.1270774

Proc Natl Acad Sci U S A. 2024 Jan 02. 121(1): e2310685120

ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.

Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.

Keywords: ANGPTL4; heterotopic ossification; leptin receptor

DOI: https://doi.org/10.1073/pnas.2310685120

Stem Cells. 2023 Dec 28. pii: sxad098. [Epub ahead of print]

Human umbilical cord mesenchymal stromal cell-derived exosomes alleviate hypoxia-induced pulmonary arterial hypertension in mice via macrophages.

Hong Liu, Qingqing Zhang, Chuanchuan Liu, Yuwei Zhang, Yuxiang Wang, Pan Huang, Lan Ma, Rili Ge.

Pulmonary hypertension (PH) is an intractable, severe, and progressive cardiopulmonary disease. Recent findings suggest that human umbilical cord mesenchymal stromal cells (HUCMSCs) and HUCMSC-derived exosomes (HUCMSC-Exos) possess potential therapeutic value for PH. However, whether they have beneficial effects on hypoxic pulmonary hypertension (HPH) is unclear. Exos are released into the extracellular environment by the fusion of intracellular multivesicular bodies with the cell membrane, and they play an important role in cellular communication. Exos ameliorate immune inflammation levels, alter macrophage phenotypes, regulate mitochondrial metabolic function, and inhibit pulmonary vascular remodelling, thereby improving PH. Macrophages are important sources of cytokines and other transmitters and can promote the release of cytokines, vasoactive molecules, and reactive oxygen species, all of which are associated with pulmonary vascular remodelling. Therefore, the aim of this study was to investigate whether HUCMSC-Exos could improve the lung inflammatory microenvironment and inhibit pulmonary vascular remodelling by targeting macrophages and identify the underlying mechanisms. The results showed that HUCMSC-Exos promoted M2 macrophage polarisation, decreased pro-inflammatory factors, increased IL-10 levels, and inhibited IL-33/ST2 axis expression, thereby inhibiting hypoxia-induced proliferation of pulmonary artery smooth muscle cells and ameliorating HPH.

Keywords: Exosomes; Hypoxic pulmonary hypertension; Immune microenvironment; Immunomodulation; Mesenchymal stromal cells; Pulmonary vascular remodelling

DOI: https://doi.org/10.1093/stmcls/sxad098