A TNF-IL-1 circuit controlsYersiniawithin intestinal granulomas

Abstract

AbstractSummaryMonocytes restrictYersiniainfection within intestinal granulomas. Here, we report that monocyte-intrinsic TNF signaling drives production of IL-1 that signals to non-hematopoietic cells to control intestinalYersiniainfection within granulomas.Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens.Yersinia pseudotuberculosiscolonizes the intestinal mucosa and induces recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas that control the bacterial infection. Inflammatory monocytes are essential for control and clearance ofYersiniawithin intestinal pyogranulomas, but how monocytes mediateYersiniarestriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following entericYersiniainfection. We further show that monocyte-intrinsic TNFR1 signaling drives production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptor on non-hematopoietic cells to enable pyogranuloma-mediated control ofYersiniainfection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative circuit as a crucial driver of intestinal granuloma function, and defines the cellular target of TNF signaling that restricts intestinalYersiniainfection.