Regulation of disease progression by ER stress

There is no current curative therapy for asbestos-induced fibrosis. Recruited monocyte-derived macrophages (MDMs)play a critical role in the pathogenesis of asbestos-induced disease progression. The activation of MDMs is dependent on their metabolic profile. Metabolic reprogramming is a key feature in macrophage activation; however, the regulation of metabolic reprogramming of macrophages in asbestos-induce fibrosis progression is poorly understood. Other than causing an alternative phenotype in certain macrophages, little is known about ER stress and UPR in lung macrophages. The effect of ER stress and UPR on metabolic reprogramming in lung fibrosis has not been investigated in any cell type, including lung macrophages. Our preliminary data show that lung macrophages from asbestosis subjects have activation of PERK (p-PERK) and absence of p-IRE1a. Asbestosis subjects also express significantly more PGC-1a in lung macrophages than normal subjects. Silencing PERK (Eif2ak3) completely abrogated PGC-1a expression in the nucleus. Asbestosis lung macrophages have increased metabolites associated with metabolic reprogramming to OXPHOS. Over expression of PERK in macrophages markedly increased OCR, while a dominant negative PERK reduced OCR. Moreover, mice harboring a conditional deletion of Eif2ak3 in MDMs are protected from asbestos-induced lung fibrosis. Based on these observations, we hypothesize that macrophage ER stress and UPR have a crucial role in asbestosis progression by increasing PERK-mediated metabolic reprogramming. Aim 1 will determine if metabolic reprogramming has a role in asbestosis progression using mice with a conditional deletion of PERK (Eif2ak3) in monocyte-derived macrophages or with a PERK inhibitor. In Aim 2, we will determine the mechanism(s) by which ER stress and UPR activates PGC-1a to mediate metabolic reprogramming. Aim 3 will determine if activation of PERK is required for FAO in lung macrophages from subjects with asbestos-induced toxicity. The studies in this proposal will provide: (a) new insights into the effect of ER stress and UPR in progression of fibrotic disease; (b) an understanding of the molecular mechanism(s) by which ER stress and UPR modulate lung macrophages to undergo metabolic reprogramming; and (c) proof-of-concept by targeting UPR genetically to disrupt metabolic reprogramming and regulate or reverse established asbestos-induced fibrosis.