Interleukin‐17/interleukin‐17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high‐fat diet‐induced metabolic syndrome model

Abstract

Sound evidence supports a role for interleukin-17 (IL-17) -producing cd T cells and IL-17-producing helper T (Th17) cells in intestinal homeostasis, especially in intestinal barrier integrity. In the present study, we aimed to evaluate the role of IL-17 cytokine in the regulation of intestinal immunity and obesity-induced metabolic syndrome (MetS) in an experimental murine model. C57BL/6 wild-type (WT) mice and mice lacking the IL-17 cytokine receptor (IL-17RA À/À ) were fed either a control diet (CD) or a high-fat diet (HFD) for 9 weeks. Our data demonstrate that IL-17RA À/À mice are protected against obesity, but develop hyperglycemia, hyperinsulinemia and insulin resistance. In parallel, HFD-fed IL-17RA À/À mice display intense inflammation in the ileum compared with WT mice on the HFD. IL-17RA À/À mice fed the HFD exhibit impaired neutrophil migration to the intestinal mucosa and reduced gene expression of the CXCL-1 chemokine and CXCR-2 receptor in the ileum. Interestingly, the populations of neutrophils (CD11b + Ly6G + ) and anti-inflammatory macrophages (CD11b + CX3CR1 + ) are increased in the mesenteric lymph nodes of these mice. IL-17RA À/À mice on the HFD also display increased commensal bacterial translocation into the bloodstream and elevated lipopolysaccharide (LPS) levels in the visceral adipose tissue (VAT). Metagenomic analysis of bacterial 16S gene revealed increased Proteobacteria and Bacteroidetes phyla, the main representatives of Gram-negative bacteria, and reduced Akkermansia muciniphila in the fecal samples of IL-17RA À/À mice fed the HFD. Together, these data indicate that the IL-17/IL-17R axis drives intestinal neutrophil migration, limits gut dysbiosis and attenuates LPS translocation to VAT, resulting in protection to MetS.

Crosstalk Among Circadian Rhythm, Obesity and Allergy

“…Additionally, allergic diseases with higher involvement of type 3 inflammation (IL-17-related response) may show a stronger correlation with obesity. This observation is supported by the failure to induce obesity in IL-17 receptor A (IL-17RA) knockout mice [76].…”

Adipokines and the control of mast cell functions: from obesity to inflammation?

“…The chronic inflammation that results from high levels of adiposity is associated with the development of a number of inflammatory conditions, mediated in part through profound effects of adipokines on a broad range of immune cells, including dendritic cells, innate lymphoid cells, and neutrophils . This new understanding of how mast cells respond to leptin and adiponectin adds another piece to this puzzle.…”

NOD2 Deficiency Promotes Intestinal CD4+ T Lymphocyte Imbalance, Metainflammation, and Aggravates Type 2 Diabetes in Murine Model

“…However, whether NOD2 genetic deficiency promotes a dysregulated gut immune environment and precipitates gut dysbiosis-driven metabolic tissue inflammation and T2D onset was not investigated. Recently, our group also demonstrated that IL-17/IL-17R axis drives intestinal neutrophil migration, limits gut dysbiosis, and attenuates LPS translocation to VAT, protecting against metabolic syndrome (42). Additionally, our group also reported that IL-23 deficient mice have reduced intestinal Th17 response, low neutrophil migration, and gut microbiota dysbiosis, resulting in increased susceptibility to obesity-induced metabolic syndrome (43).…”