IRAK-M Regulates Monocyte Trafficking to the Lungs in Response to Bleomycin Challenge

Abstract

Idiopathic pulmonary fibrosis is a deadly disease characterized by excessive extracellular matrix deposition in the lungs, resulting in decreased pulmonary function. Although epithelial cells and fibroblasts have long been the focus of idiopathic pulmonary fibrosis research, the role of various subpopulations of macrophages in promoting a fibrotic response is an emerging target. Healthy lungs are composed of two macrophage populations, tissue-resident alveolar macrophages and interstitial macrophages, which help to maintain homeostasis. After injury, tissue-resident alveolar macrophages are depleted, and monocytes from the bone marrow (BM) traffic to the lungs along a CCL2/CCR2 axis and differentiate into monocyte-derived alveolar macrophages (Mo-AMs), which is a cell population implicated in murine models of pulmonary fibrosis. In this study, we sought to determine how IL-1R-associated kinase-M (IRAK-M), a negative regulator of TLR signaling, modulates monocyte trafficking into the lungs in response to bleomycin. Our data indicate that after bleomycin challenge, mice lacking IRAK-M have decreased monocyte trafficking and reduced Mo-AMs in their lungs. Although IRAK-M expression did not regulate differences in chemokines, cytokines, or adhesion molecules associated with monocyte recruitment, IRAK-M was necessary for CCR2 upregulation following bleomycin challenge. This finding prompted us to develop a competitive BM chimera model, which demonstrated that expression of BMderived IRAK-M was necessary for monocyte trafficking into the lung and for subsequent enhanced collagen deposition. These data indicate that IRAK-M regulates monocyte trafficking by increasing the expression of CCR2, resulting in enhanced monocyte translocation into the lung, Mo-AM differentiation, and development of pulmonary fibrosis.

L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis

“…Additionally, bleomycin-treated LPL −/− lungs had lower levels of cleaved IL-1β in BAL fluid in comparison with WT mice ( Figure S3A ). To assess cellular inflammatory responses, we analyzed BAL fluid 24 h after bleomycin treatment for the influx of polymorphonuclear leukocytes (i.e., neutrophils) and depletion of AMs ( Reader et al, 2020 ; Misharin et al, 2013 ). LPL −/− mice exhibited significantly fewer CD11b + Ly6G + neutrophils in the BAL fluid ( Figure S3B ) and did not lose as many CD11c + SiglecF + AMs ( Figure S3C ) compared with WT mice.…”

Low-Dose Lung Radiation Therapy for COVID-19 Lung Disease: A Preclinical Efficacy Study in a Bleomycin Model of Pneumonitis

“…Infection or lung injury can lead to an accumulation of lung macrophages through either recruitment (42) or local proliferation in a Th2-helper environment (43). Bleomycin treatment has been shown to increase production of the chemokine CCL2 by lung cells (44,45); since migration of monocytes into inflamed lungs is dependent on CCL2/CCR2 signalling (44,45) it is reasonable to propose that LDLR might act by reducing CCL2 and/or other signals that attract monocytes into the damaged lung.…”

The role of lung macrophages in acute respiratory distress syndrome

“…IRAK-M promotes RecAMs recruitment and aggravates pulmonary fibrosis by upregulating CCR2 expression in monocytes. Conversely, gene ablation of IRAK-M reduces the recruitment of monocytes [ 128 ]. Preclinical experiments show that CCL2/CCR2 signal is a promising therapeutic target.…”