Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome

Abstract

While the ontogeny and recruitment of the intestinal monocyte/macrophage lineage has been studied extensively, their precise localization and function has been overlooked. Here we show by imaging the murine small and large intestines in steady-state that intestinal CX3CR1 + macrophages form an interdigitated network intimately adherent to the entire mucosal lamina propria vasculature. The macrophages form contacts with each other, which are disrupted in the absence of microbiome, monocyte recruitment (Ccr2 −/−), or monocyte conversion (Nr4a1 −/−). In dysbiosis, gaps exist between the perivascular macrophages correlating with increased bacterial translocation from the lamina propria into the bloodstream. The recruitment of monocytes and conversion to macrophages during intestinal injury is also dependent upon CCR2, Nr4a1 and the microbiome. These findings demonstrate a relationship between microbiome and the maturation of lamina propria perivascular macrophages into a tight anatomical barrier that might function to prevent bacterial translocation. These cells are also critical for emergency vascular repair.

Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

“…It was shown experimentally that dietary components and obesity can directly perturb the intestinal barrier by changing tight junctions in the mucosa of the gut [99]. Furthermore, CX3CR1-expressing macrophages form a perivascular barrier in the intestine, which is disrupted in dysbiosis [179]. A recent study demonstrated that the presence of CX3CR1+ macrophages in the intestine had a protective effect in models of steatohepatitis and deficiency in CX3CR1 increased steatohepatitis by elevated endotoxin levels [180].…”

From Species to Regional and Local Specialization of Intestinal Macrophages

“…LPM can be further subdivided into mucosal and submucosal LPM with different life span, transcriptional program, and functions (De Schepper et al, 2018 ). Mucosal LPM from the SI to the colon line the intestinal epithelium on the one hand and the vasculature on the other hand (Niess et al, 2005 ; Chieppa et al, 2006 ; Chikina et al, 2020 ; Honda et al, 2020 ). Mucosal subepithelial LPM are thus strategically positioned to sample luminal antigens and to protect the mucosa from enteropathogens that can penetrate the epithelial barrier.…”

“…Another subpopulation of CX 3 CR1 + mucosal and also submucosal LPM is closely associated to the intestinal vasculature in mice (De Schepper et al, 2018 ; Honda et al, 2020 ). Perivascular LPM are either self-maintaining throughout adulthood, especially submucosal ones, or replaced by monocytes on a regular basis, especially mucosal ones (De Schepper et al, 2018 ).…”

“…Perivascular LPM are either self-maintaining throughout adulthood, especially submucosal ones, or replaced by monocytes on a regular basis, especially mucosal ones (De Schepper et al, 2018 ). The full maturation of the latter from Ly6 hi monocytes is ensured by the microbiota and by the transcription factor NR4A1, a master regulator of the conversion of CCR2 hi CX 3 CR1 int Ly6C hi into CCR2 lo CX 3 CR1 hi Ly6C lo monocytes (Honda et al, 2020 ). Mucosal perivascular LPM form tight interdigitating connections around all of the vasculature of both SI and colon by which they prevent bacteria translocation into the blood circulation (Honda et al, 2020 ).…”

“…The full maturation of the latter from Ly6 hi monocytes is ensured by the microbiota and by the transcription factor NR4A1, a master regulator of the conversion of CCR2 hi CX 3 CR1 int Ly6C hi into CCR2 lo CX 3 CR1 hi Ly6C lo monocytes (Honda et al, 2020 ). Mucosal perivascular LPM form tight interdigitating connections around all of the vasculature of both SI and colon by which they prevent bacteria translocation into the blood circulation (Honda et al, 2020 ). Therefore, both subepithelial and perivascular mucosal LPM are fully equipped to prevent penetration of pathogens through epithelial and vascular barriers, offering thus a double defensive line.…”