Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis

Abstract

Macrophages are highly heterogeneous tissue-resident immune cells that perform a variety of tissue-supportive functions. The current paradigm dictates that intestinal macrophages are continuously replaced by incoming monocytes that acquire a pro-inflammatory or tissue-protective signature. Here, we identify a self-maintaining population of macrophages that arise from both embryonic precursors and adult bone marrow-derived monocytes and persists throughout adulthood. Gene expression and imaging studies of self-maintaining macrophages revealed distinct transcriptional profiles that reflect their unique localization (i.e., closely positioned to blood vessels, submucosal and myenteric plexus, Paneth cells, and Peyer's patches). Depletion of self-maintaining macrophages resulted in morphological abnormalities in the submucosal vasculature and loss of enteric neurons, leading to vascular leakage, impaired secretion, and reduced intestinal motility. These results provide critical insights in intestinal macrophage heterogeneity and demonstrate the strategic role of self-maintaining macrophages in gut homeostasis and intestinal physiology.

Nerve fiber overgrowth in patients with symptomatic diverticular disease

“…They have different phenotypic and functional features related to the needs of the microenvironment. 21 We did not find differences in immune cell counts between symptomatic and asymptomatic patients. This suggests that mucosal low-grade inflammation is merely associated with the presence of diverticula but not symptoms.…”

“…These cells arise from both embryonic precursors and adult bone marrow‐derived monocytes and persist throughout adulthood. They have different phenotypic and functional features related to the needs of the microenvironment …”

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

“…However, recent evidence in mice indicates that a separate population of CCR2‐independent intestinal macrophages exists in the gut; these are long‐lived cells that express the markers Tim4 and CD4 . These macrophages are present perinatally and play an essential role in intestinal physiology . Although definitive markers of intestinal macrophage turnover in humans have not been found, a similar hierarchy of subsets may exist in humans .…”

“…29 These macrophages are present perinatally and play an essential role in intestinal physiology. 30 Although definitive markers of intestinal macrophage turnover in humans have not been found, a similar hierarchy of subsets may exist in humans. 31 Homing of monocytes to the intestine has been proposed to be driven by inflammatory antigens originating from the diet, infection or the commensal microbiota but requirements differ depending on the setting.…”

Defining Monocyte Differentiation into Colonic and Ileal Macrophages

“…Recent studies revealed that monocyte-derived lamina propria macrophages comprise in mice two populations, i.e. short-lived cells and long-lived cells with self-renewing capacity 10 ; the latter population might also include remnants of embryonic populations, as could additional intestinal long-lived macrophage populations that reside near blood vessels, nerves and in the Peyer's patches 11 . Evidence for macrophages with different half-lives is also emerging for the human small intestine 12 .…”