Macrophage-Restricted Interleukin-10 Receptor Deficiency, but Not IL-10 Deficiency, Causes Severe Spontaneous Colitis

Abstract

Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Rα) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning agent in the colon and define intestinal CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation.

IL-10 inhibits neuraminidase-activated TGF-β and facilitates Th1 phenotype during early phase of infection

“…However, IL-10 suppresses immunity when IL-10 binds to IL-10Rs 31,34,35,44 . IL-10R expression on HA-specific CD4 þ T cells remains at the base level in the early phase of our model of influenza virus infection.…”

“…31). IL-10R1 induction upregulates IL-10R expression, which is essential for IL-10-mediated suppression 31,34,35 . Ding et al 44 demonstrated how IL-10R expression has a critical role in determining whether cells respond to IL-10.…”

“…7b). It is suggested that the upregulation of IL-10R is essential to pass immunoregulatory signals in humans and mice [31][32][33][34][35] . IL-10 imposed immune suppression as there was no substantial amount of viral NA and IL-10R that was upregulated.…”

Diversity and functions of intestinal mononuclear phagocytes

“…134 Production of GM-CSF and VEGF-C during inflammation may reprogramme the differentiation of monocytes into m that produce reparative mediators such as arginase, prostaglandins and IL-13. 200,201 Thus the overall role of the monocyte-m lineage in intestinal inflammation may reflect a balance between local pathogenic and regulatory mechanisms.…”

Gene regulatory mechanisms underlying the intestinal innate immune response

“…On the other hand, macrophages that are located deeper in the gut wall efficiently eradicate microbes that breach the intestinal epithelial barrier without mounting a potent inflammatory response. This phenotypic difference is orchestrated by interleukin-10 (IL-10), which is secreted locally by T cells, B cells, dendritic cells, and some epithelial cells to limit inflammatory responses [33,34]. The gene regulatory mechanisms controlling this behavior have been recently examined, revealing that the chromatin accessibility landscape of IL-10 knockout intestinal macrophages was similar to that of inflammatory macrophages.…”