Implicating Exudate Macrophages and Ly-6Chigh Monocytes in CCR2-Dependent Lung Fibrosis following Gene-Targeted Alveolar Injury

Abstract

The alveolar epithelium is characteristically abnormal in fibrotic lung disease, and we recently established a direct link between injury to the type II alveolar epithelial cell (AEC) and the accumulation of interstitial collagen. The mechanisms by which damage to the epithelium induces lung scarring remain poorly understood. It is particularly controversial whether an insult to the type II AEC initiates an inflammatory response that is required for the development of fibrosis. To explore whether local inflammation occurs following a targeted epithelial insult and contributes to lung fibrosis, we administered diphtheria toxin to transgenic mice with type II AEC-restricted expression of the diphtheria toxin receptor. We employed immunophenotyping techniques and diphtheria toxin receptor-expressing, chemokine-receptor-2 deficient (CCR2−/−) mice to determine the participation of lung leukocyte subsets in pulmonary fibrogenesis. Our results demonstrate that targeted type II AEC injury induces an inflammatory response that is enriched for CD11b+ non-resident exudate macrophages (ExM) and their precursors, Ly-6Chigh monocytes. CCR2-deficiency abrogates the accumulation of both cell populations and protects mice from fibrosis, weight loss, and death. Further analyses revealed that the ExM are alternatively-activated and that ExM and Ly-6Chigh monocytes express mRNA for IL-13, TGF-β, and the collagen genes, COL1A1 and COLIIIA1. Furthermore, the accumulated ExM and Ly-6Chigh monocytes contain intracellular collagen as detected by immunostaining. Together, these results implicate CCR2 and the accumulation of ExM and Ly-6Chigh monocytes as critical determinants of pulmonary fibrosis induced by selective type II AEC injury.

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

“…In addition to macrophage recruitment, MCP-1 contributes to angiogenesis and fibroblast recruitment, survival, and differentiation. CCR2 deficiency has been shown to attenuate fibrosis in WT mice in a variety of fibrosis models, including bleomycin, FITC, IL-10 overexpression, and diphtheria toxin-targeted epithelial injury (13,14,(25)(26)(27)(28)(29). Our results in HPS are largely consistent with these prior studies, but there are several key differences and advances, starting with the elucidation of cell-specific mechanisms in unchallenged HPS mice.…”

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

“…More recently, CD11c high , CD11b1 cells were shown to be recruited to the lung after LPS administration (18). Finally, Ly-6C1 monocytes and exudative macrophages have been implicated in CCR2-dependent lung fibrosis after type II cell alveolar injury (23). Whereas resolution of acute LPS-induced inflammation was characterized by restoration to a homogenous population of CD11c high , CD11b2 cells, Src homology 2 domain-containing inositol-5-phosphatase (SHIP)-1 null mice developed spontaneous chronic pulmonary inflammation characterized by CD11c high , CD11b1 alveolar macrophages and surrounding collagen deposition and alveolar wall thickening.…”

Flow Cytometric Analysis of Macrophages and Dendritic Cell Subsets in the Mouse Lung

“…An additional layer of complexity is added by the phenotypic plasticity of macrophages. Classically activated macrophages (sometimes referred to as M1-polarized) have been suggested to promote the development of acute lung injury, whereas alternatively activated macrophages (M2) may play a role in limiting or resolving lung inflammation (13) and/or potentially promoting the development of fibrosis (14)(15)(16)(17).…”