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

TY - JOUR

T1 - IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1

AU - Jenkins, Stephen J

AU - Ruckerl, Dominik

AU - Thomas, Graham D

AU - Hewitson, James P

AU - Duncan, Sheelagh

AU - Brombacher, Frank

AU - Maizels, Rick M

AU - Hume, David A

AU - Allen, Judith E

PY - 2013/10/21

Y1 - 2013/10/21

N2 - 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.

AB - 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.

KW - Adaptive Immunity

KW - Animals

KW - Cell Proliferation

KW - Filarioidea

KW - Heligmosomatoidea

KW - Homeostasis

KW - Inflammation

KW - Interleukin-4

KW - Intestines

KW - Macrophage Activation

KW - Macrophage Colony-Stimulating Factor

KW - Macrophages

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Neutrophils

KW - Receptor, Macrophage Colony-Stimulating Factor

KW - Receptors, Interleukin-4

KW - Signal Transduction

U2 - 10.1084/jem.20121999

DO - 10.1084/jem.20121999

M3 - Article

C2 - 24101381

SN - 0022-1007

VL - 210

SP - 2477

EP - 2491

JO - The Journal of experimental medicine

JF - The Journal of experimental medicine

IS - 11

ER -