Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin-4 (IL-4) signaling toward M2 macrophage-driven pulmonary fibrosis in mice

Abstract

M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the Gab family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and Gab2 were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs. Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore, conditional removal of (Gab1) and germ line knock-out of (Gab2) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1 and -2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of Gab2 suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven pulmonary fibrosis in mice. Taken together, these observations define a non-redundant role of Gab docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

“…Gab1 and Gab2 (Gab1/2) are widely expressed in various cell types, including immune cells such as T cells, and mast cells. A recent study demonstrated that the deficiency of either Gab1 or Gab2 resulted in impaired M2 polarization (53). Gab1 regulates IL-4-induced macrophage polarization by activating AKT signaling (53).…”

Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

“…Rather, STAT3 signaling is mediated, at least in part, by phosphorylated Gab2 at S623. Because of the ability to tether signaling molecules, Gab2 has been shown transmit signals to molecules such as STAT 43 . So far two phosphorylation sites on Gab2 have been implicated in STAT signaling.…”

Macrophages: friend or foe in idiopathic pulmonary fibrosis?

“…It has been well known that IL-4 is the major inducer for macrophage M2 program by activating its two major downstream signals, JAK1/STAT6 and PI3K/AKT [ 88 , 104 ]. Indeed, Guo et al reported that elevated Gab1 and Gab2 regulate IL-4-induced macrophage polarization in bleomycin-induced fibrotic lungs, with Gab1 positively regulating AKT signaling and Gab2 positively regulating STAT6 signaling [ 105 ]. Similarly, Kral et al noted that myeloid PTEN deficiency mice following bleomycin induction manifest sustained PI3K activation to enhance macrophage M2 program, leading to increased morbidity and decreased survival, although these mice exhibit impaired recruitment function [ 106 ].…”