BCL-2 Modulates IRE1α Activation to Attenuate Endoplasmic Reticulum Stress and Pulmonary Fibrosis

BCL-2 family members are known to be pro-survival agents in numerous biological settings. Here we provide evidence that in injury and repair processes in lungs, BCL-2 mainly acts to attenuate endoplasmic reticulum (ER) stress and limit extracellular matrix (ECM) accumulation. Days after intratracheal bleomycin mice lose a fraction of their alveolar type II epithelium from terminal ER stress driven by activation of the critical ER sensor and stress effector IRE1-α. This fraction is dramatically increased by BCL-2 inhibition because IRE1-α activation is dependent on its physical association with the BCL-2-pro-apoptotic family member BAX and we found BCL-2 to disrupt this association in vitro. In vivo, Navitoclax (a BCL-2/BCL-xL inhibitor) given 15-21 days after bleomycin challenge evoked strong activation of IRE-1α in mesenchymal cells and markers of ER stress but not apoptosis. Remarkably, following BCL-2 inhibition, bleomycin-exposed mice demonstrated persistent collagen accumulation at day 42 compared to resolution in controls. Enhanced fibrosis proved to be due to the RNAase activity of IRE1a downregulating MRC2 mRNA and protein, a mediator of collagen turnover. The critical role of MRC2 was confirmed in PCLS cultures of day 42 lungs from bleomycin-exposed WT and MRC2 null mice. Soluble and tissue collagens accumulated in PCLS cultures from Navitoclax-treated, bleomycin challenged mice compared to controls, nearly identical to that of challenged but untreated MRC2 nulls. Thus, apart from mitochondrial-based anti-apoptosis, BCL-2 functions to attenuate ER stress responses, fostering tissue homeostasis and injury repair.