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The IL-10 receptor inhibits cell extrinsic signals necessary for STAT1-dependent macrophage accumulation during colitis.

ABSTRACT: The loss of IL-10R function leads to severe early onset colitis and, in murine models, is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed, STAT1^-/- mice exhibit defects in colonic macrophage accumulation after Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNγR, an inducer of STAT1 activation. Radiation chimeras demonstrated that reduced accumulation of STAT1-deficient macrophages was based on a cell-intrinsic defect. Unexpectedly, mixed radiation chimeras generated with both wild-type and IL-10R-deficient bone marrow indicated that rather than directly interfering with STAT1 function, IL-10R inhibits the generation of cell extrinsic signals that promote the accumulation of immature macrophages. These results define the essential mechanisms controlling the inflammatory macrophage accumulation in inflammatory bowel diseases.

SUBMITTER: Patik I

PROVIDER: S-EPMC10431098 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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The IL-10 receptor inhibits cell extrinsic signals necessary for STAT1-dependent macrophage accumulation during colitis.

Patik Izabel I Redhu Naresh S NS Eran Alal A Bao Bin B Nandy Anubhab A Tang Ying Y El Sayed Shorouk S Shen Zeli Z Glickman Jonathan J Fox James G JG Snapper Scott B SB Horwitz Bruce H BH

Mucosal immunology 20230302 3

The loss of IL-10R function leads to severe early onset colitis and, in murine models, is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed, STAT1<sup>-/-</sup> mice exhibit defects in colo ...[more]

PMID: 36868479

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Project description:IntroductionElevated interleukin-6 (IL-6) plasma levels have been associated with abdominal aortic aneurysm (AAA), but whether this cytokine plays a causative role in the degenerative remodeling or represents an effect from the inflammatory cascades initiated by infiltrating leukocytes remained unclear. This project aims to demonstrate that within the aortic wall, signaling from IL-6 through the STAT3 transcription factor is necessary for infiltration of proteolytically-active macrophages and development of small AAA.MethodsFollowing measurement of baseline infrarenal aortic diameter (AoD, digital microscopy), C57Bl/6 and IL-6 knockout (IL-6KO) mice underwent AAA induction by application of peri-adventitial CaCl2 (0.5 M) +/- implantation of an osmotic mini-pump delivering IL-6 (4.36 µg/kg/day over 21 days). At the terminal procedure, AoDs were measured by digital microscopy and aortas harvested for immunoblot (pSTAT3/STAT3), matrix metalloproteinase (MMP) quantification, or flow cytometric analysis of macrophage content. Plasma was collected for cytokine analysis.ResultsIL-6 infusion significantly increased the plasma IL-6 levels in C57Bl/6 and IL-6KO animals. The C57Bl/6 + CaCl2 group developed AAA (AoD >50% above baseline) but IL-6KO + CaCl2 did not. In the IL-6KO + IL-6+CaCl2 group, AAA developed to match that of C57Bl/6 + CaCl2 mice. STAT3 activity was significantly increased in animals with advanced stages of dilation (>40% from baseline), compared to those with ectasia (≤25%). Although cytokine profiles did not support T-cells or neutrophils as being active contributors in this stage of aortic remodeling, changes in the profile of elaborated MMPs suggested macrophage activity with a trend toward alternatively activated pathways. Flow cytometry confirmed significantly increased macrophage abundance specifically in animals with upregulated STAT3 activity and advanced aortic dilation.ConclusionIn this murine model of AAA, progressive dilation to development of true AAA was only accomplished when IL-6 signaling upregulated STAT3 activity to effect accumulation of proteolytically-active macrophages. This pathway warrants further investigation to identify potential therapeutic avenues to abrogate growth of small AAA.

Dataset Information

The IL-10 receptor inhibits cell extrinsic signals necessary for STAT1-dependent macrophage accumulation during colitis.

Publications

The IL-10 receptor inhibits cell extrinsic signals necessary for STAT1-dependent macrophage accumulation during colitis.

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