BAG3: a new biomarker of interstitial lung disease and possible therapeutic target for tissue fibrosis

ILDs encompass heterogeneous disorders with various clinical courses. Idiopathic pulmonary fibrosis is a prototype of progressive fbrosing ILD with a poor prognosis. However, fibrosing ILDs other than IPF, including autoimmune ILDs, also have a progressive phenotype, with high morbidity and mortality. Current understanding is limited regarding the pathogenesis of PF-ILDs. Some ILDs are primarily fibrotic, while other ILDs are predominantly inflammatory disorders but can shift to a fibrotic pathway at a later stage. Although the initial pathogenetic mechanisms are distinct among different PF-ILDs, the processes resulting in self-sustaining fibrosis and organ damage are likely to be common. Specifically, persistent and unregulated yofibroblasts that fail to undergo apoptosis contribute via excessive deposition of connective proteins to lung tissue structural and mechanical changes (remodeling), resulting in the loss of alveolar function. The fibrosing process eventually becomes self-perpetuating, as increased lung tissue stiffness and damage further recruits and activates myofibroblasts. Persistent myofibroblast activity contributes to excessive deposition of the extracellular matrix and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Among cytokines, TGF-ß drives the differentiation of fibroblasts into apoptosis- resistant myofibroblasts and sustains the production of extracellular matrix components. Several serum biomarkers have been tested for their ability to predict disease progression, but no molecule has been validated as a prognostic marker for use in clinical practice so far. Importantly, while many therapeutic targets are measurable, biomarkers that reflect the activity of these therapeutic targets on specific cells in specific tissues may ultimately be more informative than the targets themselves. Bcl2-associated athanogene 3 (BAG3) protein is a member of the BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein-70 through BAG domain. BAG3 is constitutively present in a few normal cell types and some tumors, while its expression is induced by stressful stimuli in a wide variety of cells. BAG3 interacts with several partner proteins regulating different pathways, including apoptosis, autophagy and motility. Recent studies suggest that BAG3 can directly and/or indirectly regulate the fibrotic processes. Our study will shed light on the validity of BAG3 protein as a serum biomarker and therapeutic target in PF-ILD patients. We aim to determine the sefulness of the proposed biomarker in clinical practice to indicate disease progression, adoption of aggressive therapies and to assess drug effects. We will analyze the plasmamembrane expression of BAG3R and its ability to activate the signaling pathway in fibroblasts from SSc patients compared to healthy donors, and the ability of BAG3 to induce collagen production and release in these cells. We will also test whether SSc fibroblasts express and secrete BAG3, activating an autocrine circuit. Furthermore, we will study the functional connection of BAG3 and TGFbeta-mediated pathways. Finally, we will evaluate the effect of BAG3 blockade in an in vivo model of bleomycin-induced fibrosis. The therapeutic efficacy of anti-BAG3 humanized antibodies in animal models might suggest a promising diseasemodified agent in the landscape of PF-ILDs anti-fibrotic options.