Differential Roles of Chi3l1 and its receptors in COPD and IPF

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ABSTRACT COPD and fibrotic disorders like idiopathic pulmonary fibrosis (IPF) have remarkably different pathologies with the former characterized by tissue loss and the latter by interstitial fibrosis and excess matrix deposition. However, recent studies highlighted a subgroup of patients with COPD with both emphysema and interstitial lung abnormalities (ILA) and demonstrated that injury and repair play critical roles in both disorders. They also demonstrated that TGF-β1 is a mediator that is dysregulated in both that has the surprising ability to drive fibrosis while augmenting tissue injury and cell death. To define the mechanisms that determine if TGF-β1 cause emphysema and or fibrosis, we generated lung-targeted TGF-β1 transgenic (Tg) mice on 10 inbred genetic backgrounds. Using In silico haplotype evaluations and expression microarray analysis on these mice, we have identified genes associated with TGF-β1-induced fibrosis or emphysema. Interestingly, the studies of these TGF- β1 genetic modifiers all led to the prototypic chitinase-like protein, chitinase 3-like-1 (Chi3l1) and its receptors. To further understand the role(s) of the Chi3l1 axis in emphysema and fibrosis, recent studies have focused on the biology of Chi3l1 and its receptors. These studies demonstrated that; (1) Chi3l1 is induced at sites of injury and repair where it inhibits injury while fostering repair, (2) In cigarette smoke (CS)-induced emphysema and bleomycin responses, Chi3l1 inhibits epithelial cell death and tissue destruction and drives tissue fibrosis respectively, (3) The effects of Chi3l1 are mediated by 2 different receptors, a multimeric complex called the chitosome that regulates cell death and CRTH2 which drives fibroproliferative repair, (4) The chitosome has one alpha subunit (IL-13Rα2) and 2 different β subunits, TMEM219 (TMEM) and galectin 3 (Gal3), which competes with TMEM for IL-13Rα2 binding. Our most recent studies have also highlighted phosphorylated and non- phosphorylated forms of Chi3l1, demonstrated that the components of the chitosome are regulated by epigenetic modifications and highlighted relationships between the Chi3l1 axis and mitochondria. These findings led to the overall hypothesis for this project: The differential expression, utilization and or phosphorylation of Chi3l1 and its receptors play major roles in the generation of the divergent outcomes of fibrosis and emphysema. To address this hypothesis, we will (Aim#1) characterize the relationships between the fibrosis-associated and emphysema- associated TGF-β1 genetic modifiers and Chi3l1 and its receptors in the lung at baseline, after exposure to CS or TGF-β1, and in animal models of fibrosis and emphysema, (Aim#2) characterize the site, mechanism and consequences of Chi3l1 activation/deactivation via cyclin-dependent kinase (CDK), the phosphatase PP2A & FAM13A, (Aim #3) characterize the importance of IL-13Rα2 glycosylation and epigenetic modifications of IL- 13Rα2 and TMEM in the trafficking, binding and effector responses of Chi3l1, (Aim #4) characterize the interactions between the Chi3l1 axis and mitochondria; specifically, how mitochondria regulate the Chi3l1 axis and how the axis regulates mitochondrial function, dynamics, biogenesis, metabolism, and mitophagy.