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

Macrophages (M Phi s) 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 M Phi s during a Th2-biased tissue nematode infection. We now show that proliferation of M Phi s during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires M Phi-intrinsic IL-4R signaling. However, both IL-4R alpha-dependent and -independent mechanisms contributed to M Phi proliferation during nematode infections. IL-4R-independent proliferation was controlled by a rise in local CSF-1 levels, but IL-4R alpha expression conferred a competitive advantage with higher and more sustained proliferation and increased accumulation of IL-4R alpha(+) compared with IL-4R alpha(-) cells. Mechanistically, this occurred by conversion of IL-4R alpha(+) M Phi s from a CSF-1-dependent to -independent program of proliferation. Thus, IL-4 increases the relative density of tissue M Phi s by overcoming the constraints mediated by the availability of CSF-1. Finally, although both elevated CSF1R and IL-4R alpha 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 M Phi numbers without coincident monocyte recruitment.