Constant Replenishment from Circulating Monocytes Maintains the Macrophage Pool in the Intestine of Adult Mice

Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D, Mowat AM.

Nat Immunol. 2014 Aug 24. doi: 10.1038/ni.2967.

From the Left to Right: Calum Bain, Allan Mowat and Alberto Bravo Blas

From the Left to Right: Calum Bain, Allan Mowat and Alberto Bravo Blas

The normal intestine contains large numbers of macrophages that play crucial roles in homeostasis, by clearing dying epithelial cells and microbes, as well as producing trophic factors for the epithelium. Constitutive production of IL-10 and refractoriness to stimulation by eg TLR ligands allows these processes to occur without provoking inflammation. However macrophages have also been implicated in inflammatory conditions such as IBD and it has been unclear if this requires separate populations, or if the resident macrophages can become pro-inflammatory. Recently a paradigm has arisen that resident macrophages in healthy tissues are derived from embryonic precursors that then self renew in situ throughout life. According to this idea, monocytes are responsible only for generating the macrophages involved in inflammation. However in previous work, we showed that adoptively transferred, Ly6Chi “classical” monocytes could enter the healthy lamina propria, where they then differentiated from a pro-inflammatory state into resident macrophages. This differentiation process appeared to be arrested during inflammation, suggesting that monocytes could give rise to both homeostatic and inflammatory macrophages depending on the circumstances. The current work using lineage tracking reporter gene mice, bone marrow chimeras and parabiotic approaches, shows conclusively that the adult macrophage pool in the healthy intestine requires constant replenishment by monocytes. This process begins around weaning, is dependent on the CCR2 chemokine receptor and is partly driven by the microbiota. Altogether, this makes macrophages in the intestine quite distinct from their counterparts elsewhere. However it makes sound biological sense, as the constant exposure of the intestine to environmental agents warrants continuous monitoring by myeloid precursors with high plasticity. PubMed: 25151491