Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production

Abstract

C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor β (TGF-β) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-β secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…ER stress develops in airway cells in this model and is exacerbated by viral infection, and the UPR has been associated with the differentiation status of macrophages, and intrinsic ER stress within macrophages also occurs 16, 71, 75, 83, 84, 85, 86…”

“…). Evidence for ER stress in human respiratory epithelial cells, particularly in type II pneumocytes, includes high expression of CHOP,71 activation of ATF6, XBP1 and ATF4 14. Activation of the UPR has been found in both inherited and sporadic IPF and associated with viral infection 13.…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…Changes in proteostasis lead to an increase of nonfunctional proteins, accumulation of cytotoxic proteins, and/or aggregation of misfolded proteins. In IPF lungs, evidence of altered proteostasis has been found at different levels, including protein misfolding, markers of ER stress (99)(100)(101)(102), defective autophagy, and impaired proteasome activity (103,104) (Table 4). For instance, familial pulmonary fibrosis is associated with several mutations in surfactant A and C genes (105)(106)(107)(108).…”

Endoplasmic reticulum stress in lung disease

“…Mutation of the COPA gene, which encodes a protein involved in Golgi-to-ER retrieval was found to cause autoimmune arthritis and pulmonary interstitial lung disease, but although UPR activation was detected in the lung epithelium the mutation caused a multisystem disorder of altered immune function [15]. In two separate studies, the UPR transcription factor CHOP has been identified as a potential driver of fibrosis [16,61]. Deletion of Chop in mice reduced alveolar epithelial apoptosis following bleomycin treatment, but in one of the studies adoptive transfer of wildtype macrophages restored normal levels of pulmonary fibrosis [16].…”

“…In two separate studies, the UPR transcription factor CHOP has been identified as a potential driver of fibrosis [16,61]. Deletion of Chop in mice reduced alveolar epithelial apoptosis following bleomycin treatment, but in one of the studies adoptive transfer of wildtype macrophages restored normal levels of pulmonary fibrosis [16]. This suggests that modulation of the innate immune response by CHOP in the macrophage may play an important role, at least in the bleomycin model of fibrosis.…”