mBio (Oct 2023)
M2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice
Abstract
ABSTRACT Toll-like receptor 4 (TLR4) is an innate immune receptor responsive to lipopolysaccharide (LPS). Single nucleotide polymorphisms (SNPs) in human TLR4 that encode an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I) render individuals hyporesponsive to LPS. In humans, these SNPs are also associated with increased susceptibility to inflammatory bowel diseases (IBDs). Using knock-in mice engineered to express the murine homologs of these human TLR4 mutations (“TLR4-SNP” mice), we have shown that TLR4-SNP mice develop significantly more severe colitis induced by dextran sodium sulfate (DSS) than wild-type (WT) mice, similar to IBD in humans expressing these SNPs. Previous studies have provided indirect evidence for “tissue repair” M2 macrophages (Mφ) in the resolution of colitis. Signaling through the IL-4/IL-13 receptor, IL-4Rα, and the transcription factor, peroxisome proliferator-activated receptor (PPARγ), have been shown to be required for induction of M2a Mφ, and our data provide direct evidence for the involvement of both in the repair of DSS-induced colonic damage. In response to DSS, colons of TLR4-SNP mice produced reduced levels of M2a Mφ marker mRNA and protein, including PPARγ, and therapeutic administration of the PPARγ agonist ligand, rosiglitazone, resolved colitis in TLR4-SNP mice, and increased expression of the M2a protein, Ym1. Together, these data indicate that the failure of TLR4-SNP mice to resolve DSS-induced colitis may be secondary to their failure to induce “tissue repair” M2a Mφ. Importance Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, impacts millions of individuals worldwide and severely impairs the quality of life for patients. Dysregulation of innate immune signaling pathways reduces barrier function and exacerbates disease progression. Macrophage (Mφ) signaling pathways are potential targets for IBD therapies. While multiple treatments are available for IBD, (i) not all patients respond, (ii) responses may diminish over time, and (iii) treatments often have undesirable side effects. Genetic studies have shown that the inheritance of two co-segregating SNPs expressed in the innate immune receptor, TLR4, is associated with human IBD. Mice expressing homologous SNPs (“TLR4-SNP” mice) exhibited more severe colitis than WT mice in a DSS-induced colonic inflammation/repair model. We identified a critical role for M2a “tissue repair” Mφ in the resolution of colitis. Our findings provide insight into potential development of novel therapies targeting Mφ signaling pathways that aim to alleviate the debilitating symptoms experienced by individuals with IBD.
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