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J Exp Med. 2013 Oct 21;210(11):2477-91. doi: 10.1084/jem.20121999. Epub 2013 Oct 7.

IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1.

Author information

1
Institute of Immunology and Infection Research, School of Biological Sciences; and 2 Medical Research Council Centre for Inflammation Research and 3 The Roslin Institute and Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine; University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.

Abstract

Macrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling. However, both IL-4Rα-dependent and -independent mechanisms contributed to MΦ proliferation during nematode infections. IL-4R-independent proliferation was controlled by a rise in local CSF-1 levels, but IL-4Rα expression conferred a competitive advantage with higher and more sustained proliferation and increased accumulation of IL-4Rα(+) compared with IL-4Rα(-) cells. Mechanistically, this occurred by conversion of IL-4Rα(+) MΦs from a CSF-1-dependent to -independent program of proliferation. Thus, IL-4 increases the relative density of tissue MΦs by overcoming the constraints mediated by the availability of CSF-1. Finally, although both elevated CSF1R and IL-4Rα signaling triggered proliferation above homeostatic levels, only CSF-1 led to the recruitment of monocytes and neutrophils. Thus, the IL-4 pathway of proliferation may have developed as an alternative to CSF-1 to increase resident MΦ numbers without coincident monocyte recruitment.

PMID:
24101381
PMCID:
PMC3804948
DOI:
10.1084/jem.20121999
[Indexed for MEDLINE]
Free PMC Article

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