Gut-resident CX3CR1 ^hi macrophages induce tertiary lymphoid structures and IgA response in situ

Abstract

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2+CX3CR1lo, Ccr7+CX3CR1int (lymph migratory), and Cxcl13+CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13+CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7+CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.

Regulation and function of CX3CR1 and its ligand CX3CL1 in kidney disease

“…A recent publication addresses the role of CX3CR1 + cells in induction of tertiary lymphoid structures and IgA response in salmonella colitis and determined a mechanistic requirement of the CX3CR1 HIGH expressing subtype (Koscsó et al 2020). However, while CX3CR1promotor-driven Cre-recombinases were used to assess the role of antigen presentation by this cell type, the study did not address the functional role of the CX3CR1 molecule itself in this process.…”

Epithelium-autonomous NAIP/NLRC4 prevents TNF-driven inflammatory destruction of the gut epithelial barrier in Salmonella-infected mice

“…This includes the protective effect of the mucus, 9 , 18 , 19 the secretion of antimicrobial peptides, 20 the recruitment of neutrophils and other inflammatory cell types to eliminate the pathogen, 21 – 23 and the production of pathogen-specific IgA that accelerates pathogen clearance from the lumen. 24 , 25 In addition, experiments both in vivo and in cultured cells have revealed that inflammasomes, made up of NOD-like receptors (NLRs) and/or inflammatory caspases, are of central importance in the S .Tm-infected mucosa. 26 Several distinct inflammasomes, including canonical NLR/Caspase-1 inflammasomes 27 – 39 and non-canonical Caspase-11 (Caspase-4/5 in human) inflammasomes 29 , 31 , 40 have been implicated during S .Tm gut infection.…”

Dynamic expression of smRNA from fecal exosome in disease progression of an inflammatory bowel disorder mouse model

“…In summary, our study proposes that fecal exosomal smRNA profiling offers a new groundbreaking opportunity to monitor the inflammatory status of the gut with a capability of detecting its pro-inflammatory (asymptomatic) status. IBD is considered to progress slowly with spatiotemporally dynamic interplay of multiple subsets of immune cells (28). Our next step is to understand from which cells these exosomes are secreted and their physiological impact in vivo.…”