bims-nastce 2022-01-30 papers

Immunometabolism. 2021 ;pii: e220002. [Epub ahead of print]4(1):

T Regulatory Cells in the Visceral Adipose Tissues.

CD4+ Foxp3+ T regulatory cells (Tregs) residing in the visceral adipose tissues (VAT) have profound effects on local and systemic metabolism. Although many of the molecular characteristics of VAT resident Tregs have been identified, how these cells promote metabolic homeostasis is still unclear. Several new publications help to illuminate the molecular mechanisms that underpin VAT resident Treg function and will be discussed here.

Keywords: Tregs; adipose tissue; metabolism; obesity

DOI: https://doi.org/10.20900/immunometab20220002

Immunity. 2022 Jan 20. pii: S1074-7613(21)00552-5. [Epub ahead of print]

IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment.

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.

Keywords: ATOH1; IL-17A; Lgr5; Th17; intestine; organoids; progenitor cells; secretory cell lineage; stem cell

DOI: https://doi.org/10.1016/j.immuni.2021.12.016

J Hepatol. 2022 Jan 21. pii: S0168-8278(22)00007-1. [Epub ahead of print]

Liver Stromal Cells Restrict Macrophage Maturation and Stromal IL-6 Limits the Differentiation of Cirrhosis-linked Macrophages.

Erica Buonomo, Shenglin Mei, Samantha Guinn, Isabelle Leo, Michael Peluso, Mei-An Nolan, Frank Schildberg, Lei Zhao, Christine Lian, Shuyun Xu, Joseph Misdraji, Peter Kharchenko, Arlene Sharpe.

BACKGROUND AND AIMS: Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of stromal-myeloid coculture systems to study these interactions in the context of cirrhosis.
METHODS: Single cell RNA sequencing analyses of noncirrhotic (n=7) and cirrhotic (n=5) human liver tissue was correlated to the bulk RNA sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems.
RESULTS: We find that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer Cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in healthy liver.
CONCLUSIONS: Our work reveals an unanticipated role for liver stromal cells to impede the maturation and alter the differentiation of macrophages and prompts investigation into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis.
LAY SUMMARY: The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using scRNA-seq analysis of cirrhotic and noncirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and stromal-secreted IL-6 in limiting the differentiation of a cirrhotic macrophage subset.

Keywords: IL-6; Liver cirrhosis; human; macrophage differentiation; macrophage maturation; myeloid cells; single cell RNA-seq; stromal cells

DOI: https://doi.org/10.1016/j.jhep.2021.12.036

World J Hepatol. 2021 Dec 27. 13(12): 1956-1967

Liver manifestations and complications in inflammatory bowel disease: A review.

Rui Gaspar, Catarina Castelo Branco, Guilherme Macedo.

Hepatobiliary manifestations are common in inflammatory bowel disease (IBD), with 30% of patients presenting abnormal liver tests and 5% developing chronic liver disease. They range from asymptomatic elevated liver tests to life-threatening disease and usually follow an independent course from IBD. The pathogenesis of liver manifestations or complications and IBD can be closely related by sharing a common auto-immune background (in primary sclerosing cholangitis, IgG4-related cholangitis, and autoimmune hepatitis), intestinal inflammation (in portal vein thrombosis and granulomatous hepatitis), metabolic impairment (in non-alcoholic fatty liver disease or cholelithiasis), or drug toxicity (in drug induced liver injury or hepatitis B virus infection reactivation). Their evaluation should prompt a full diagnostic workup to identify and readily treat all complications, improving management and outcome.

Keywords: Crohn's disease; Drug induced liver injury; Hepatobiliary manifestations; Inflammatory bowel disease; Primary sclerosing cholangitis; Ulcerative colitis; Viral hepatitis

DOI: https://doi.org/10.4254/wjh.v13.i12.1956

Front Cardiovasc Med. 2021 ;8 824481

Oxidized Lipids: Common Immunogenic Drivers of Non-Alcoholic Fatty Liver Disease and Atherosclerosis.

Constanze Hoebinger, Dragana Rajcic, Tim Hendrikx.

The prevalence of non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to inflammatory steatohepatitis (NASH) and cirrhosis, continues to rise, making it one of the major chronic liver diseases and indications for liver transplantation worldwide. The pathological processes underlying NAFLD not only affect the liver but are also likely to have systemic effects. In fact, growing evidence indicates that patients with NAFLD are at increased risk for developing atherosclerosis. Indeed, cardiovascular complications are the leading cause of mortality in NAFLD patients. Here, we aim to address common pathophysiological molecular pathways involved in chronic fatty liver disease and atherosclerosis. In particular, we focus on the role of oxidized lipids and the formation of oxidation-specific epitopes, which are important targets of host immunity. Acting as metabolic danger signals, they drive pro-inflammatory processes and thus contribute to disease progression. Finally, we summarize encouraging studies indicating that oxidized lipids are promising immunological targets to improve intervention strategies for NAFLD and potentially limit the risk of developing atherosclerosis.

Keywords: NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); atherosclerosis; foamy macrophages; immunoglobulins; oxidized lipids

DOI: https://doi.org/10.3389/fcvm.2021.824481