Intracellular Osteopontin induces Pathologic Macrophage phenotypes in Pulmonary Fibrosis

Duke University, Durham NC

Investigators

Abstract

PROJECT SUMMARY Although treatments have been approved, the etiology idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease with extremely poor outcomes, remains elusive and patient wellbeing continues to decline on therapy. Further, non-specific steroid treatment has increased IPF mortality, highlighting the need for deeper mechanistic understanding of IPF initiation and progression. Many human and in vivo modeling studies have identified a central role for alveolar macrophages in the promotion of pulmonary fibrosis through the cytokine- mediated activation and polarization of fibroblasts. Further, osteopontin (OPN, Spp1 gene) upregulation is a hallmark finding in IPF biopsies and mouse models and commonly defines pro-fibrotic alveolar macrophages. Crucially, our lab has identified that OPN has two functionally distinct isoforms generated by alternative translation. Pulmonary fibrosis studies of OPN thus far almost exclusively analyze the summative actions of the secreted (sOPN) and intracellular (iOPN) isoforms. While some possible sOPN functions have been described in vitro, the role of iOPN remains entirely unexplored in pulmonary fibrosis. Our recent preliminary data has identified that iOPN activates mTOR, promotes a fibrotic macrophage phenotype, and is sufficient to induce disease in vivo. Further, my data suggest that OPN is essential for the development of Trained Immunity. As an innate immune memory program, Trained Immunity confers enhanced secondary responses from inflammation- experienced myeloid cells. Given that IPF is thought to involve repeated epithelial injury, resident immune cells are likely trained to form memory of the sequential inflammation. These immunological adaptations of resident cells may represent a mechanism of disease progression due to each exacerbation producing cycles of epithelial injury, alveolar macrophage training, and enhanced collagen deposition by activated fibroblasts. These data indicate that the previously unrecognized iOPN isoform may represent a central regulator of fibrosis induction and disease progression, explaining, in part, its consistent association with IPF severity. In this proposal, I will uncover the mechanism of iOPN-dependent mTOR activation and Trained Immunity and determine their contribution to lung fibrosis pathology in vivo. By studying the isoform-specific roles of OPN in pulmonary fibrosis, this research will bring crucial mechanistic context to our understanding of IPF pathophysiology and has the potential to illuminate new therapeutic targets.