Origin, Differentiation, and Function of Intestinal Macrophages.

Macrophages are increasingly recognized as essential players in the maintenance of intestinal homeostasis and as key sentinels of the intestinal immune system. However, somewhat paradoxically, they are also implicated in chronic pathologies of the gastrointestinal tract, such as inflammatory bowel disease (IBD) and are therefore considered potential targets for novel therapies. In this review, we will discuss recent advances in our understanding of intestinal macrophage heterogeneity, their ontogeny and the potential factors that regulate their origin. We will describe how the local environment of the intestine imprints the phenotypic and functional identity of the macrophage compartment, and how this changes during intestinal inflammation and infection. Finally, we highlight key outstanding questions that should be the focus of future research.

Expression and characterization of αvß5 integrin on intestinal macrophages.

Macrophages play a crucial role in maintaining homeostasis in the intestine, but the underlying mechanisms have not yet been elucidated fully. Here, we show for the first time that mature intestinal macrophages in mouse intestine express high levels of αvß5 integrin, which acts as a receptor for the uptake of apoptotic cells and can activate molecules involved in several aspects of tissue homeostasis such as angiogenesis and remodeling of the ECM. αvß5 is not expressed by other immune cells in the intestine, is already present on intestinal macrophages soon after birth, and its expression is not dependent on the microbiota. In adults, αvß5 is induced during the differentiation of monocytes in response to the local environment and it confers intestinal macrophages with the ability to promote engulfment of apoptotic cells via engagement of the bridging molecule milk fat globule EGF-like molecule 8. In the absence of αvß5, there are fewer monocytes in the mucosa and mature intestinal macrophages have decreased expression of metalloproteases and IL 10. Mice lacking αvß5 on haematopoietic cells show increased susceptibility to chemical colitis and we conclude that αvß5 contributes to the tissue repair by regulating the homeostatic properties of intestinal macrophages.

Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities.

Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80(hi)GATA6(+) macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C(+) monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80(lo)MHCII(+) cells that act, in part, as precursors of F4/80(hi)GATA6(+) macrophages. Notably, monocyte-derived F4/80(hi) macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.