Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by cellular phenotype alterations and deposition of extracellular matrix proteins. The alternative activation of macrophages in the lungs has been associated as a major factor promoting pulmonary fibrosis, however the mechanisms underlying this phenomenon are poorly understood. In the present study, we have defined a molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin lead to the activation of Rac2 which regulates alternative macrophage differentiation, a signaling axis within the pulmonary macrophage compartment required for bleomycin induced pulmonary fibrosis. Mice deficient in Rac2 were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers. We have demonstrated a macrophage autonomous process by which the injection of M2 and not M1 macrophages restored the bleomycin induced pulmonary fibrosis susceptibility in Rac2-/- mice, establishing a critical role for a macrophage Rac2 signaling axis in the regulation of macrophage differentiation and lung fibrosis in vivo. We also demonstrate that markers of alternative macrophage activation are increased in patients with IPF. Taken together, these studies define an important role for an integrin-driven Rac2 signaling axis in macrophages, and reveal that Rac2 activation is required for polarization of macrophages towards a profibrotic phenotype and progression of pulmonary fibrosis in vivo.

C/EBP Homologous Protein (CHOP) Activates Macrophages and Promotes Liver Fibrosis inSchistosoma japonicum-Infected Mice

“…Gong and his team found that excretory secretion of antigen (ES) from Schistosoma japonicum eggs can activate macrophages to exhibit enhanced M2b polarization [47]. It has been reported that reducing or even eliminating mice macrophages can reduce organ fibrosis [52, 53], while M2 macrophage adoptive transplantation can aggravate organ fibrosis in mice [54, 55]. Moreover, the decrease in the infiltration of M2 macrophages can be observed in the CHOP −/− animal fibrosis model [18, 56, 57].…”

<p>Myelin basic protein charge isomers change macrophage polarization</p>

“…There is some evidence that small GTPase Rac controls the polarization of M2 macrophages 23,24. Signals transmitted from the extracellular matrix via the α4β1-integrin lead to the activation of Rac which regulates alternative macrophage differentiation into M2 phenotype.…”

Injectable Gelatin Hydrogel Suppresses Inflammation and Enhances Functional Recovery in a Mouse Model of Intracerebral Hemorrhage

“…For example, in the tumor microenvironment, interstitial flow through the integrin β1 promotes autophosphorylation of FAK, which activates downstream Src/Akt, and transmits the signal to STAT3/6, thus promoting the M2-type polarization of macrophages (Li et al, 2018). In the pulmonary fibrosis model, the extracellular matrix via the α4β1 integrin leads to the activation of Rac2 and potentially regulates macrophage M2 differentiation (Joshi et al, 2017). In the colitis model, the Integrin αVβ3 polarized macrophages toward M1-type by promoting the overactivation of STAT1/3 downstream of the ILK/Akt/mTOR signaling pathway (Piedra-Quintero et al, 2019).…”