Myeloid Cell Recruitment Represents A Covergent Pathway For Early Inflammation In Mice Expressing Mutant Surfactant Protein-C Isoforms

Patients with interstitial lung disease (ILD) often experience one or more episodes of precipitous deterioration (“acute exacerbations” or AE-ILD) marked by polycellular alveolitis and diffuse lung injury. We developed two preclinical models expressing distinct functional classes of ILD associated mutations in the alveolar type 2 (AT2) cell specific Surfactant Protein C [SP-C] gene [SFTPC] residing in the carboxy-terminus of the SP-C propeptide. Tamoxifen treatment of adult Inducible-SP-C mice rapidly upregulated both mutant proSP-C isoforms. Whereas AT2 cells isolated from I-SftpcI73T mice demonstrated mistrafficked proSP-C on the plasma membrane and a block in autophagy, AT2 cells from I-SftpcC121G produced ER retained proSP-C isoforms and activated ER stress pathways. Despite the differences, both classes of mutations induced an early multiphasic alveolitis marked by sequential accumulation of SiglecFloCD11b+CD64-CD11c-Ly6C+ monocytes (3d), LY6G+ neutrophils (7d) and SiglecFhiCD11bhiCD11clo eosinophils (2wk) in concert with histologically diffuse parenchymal lung injury. Ccl2 mRNA was upregulated early in both models in association with elevated BALF MCP-1 protein. Pretreatment of I-SftpcI73T mice with IV clodronate prior to induction resulted in attenuation of tissue related CCR2+ monocytes with improved survival and decreased BALF cell counts at 3d and 7d. Together these models provide proof of concept for AT2 dysfunction in AE-ILD pathogenesis converging at the level of early MCP-1 production and monocyte recruitment supporting a deleterious role for an AT2-monocyte axis in Sftpc mediated lung injury.