Epithelial Expression of an Interstitial Lung Disease–Associated Mutation in Surfactant Protein-C Modulates Recruitment and Activation of Key Myeloid Cell Populations in Mice

Abstract

Patients with idiopathic pulmonary fibrosis (IPF) often experience precipitous deteriorations, termed "acute exacerbations" (AE), marked by diffuse alveolitis and altered gas exchange, resulting in a significant loss of lung function or mortality. The missense isoleucine to threonine substitution at position 73 (I73T) in the alveolar type 2 cell-restricted surfactant protein-C (SP-C) gene (SFTPC) has been linked to clinical IPF. To better understand the sequence of events that impact AE-IPF, we leveraged a murine model of inducible SP-C I73T (SP-C I73T/I73T Flp +/2) expression. Following administration of tamoxifen to 8-12-wk-old mice, an upregulation of Sftpc I73T initiated a diffuse lung injury marked by increases in bronchoalveolar lavage fluid (BALF) protein and histochemical evidence of CD45 + and CD11b + cell infiltrates. Flow cytometry of collagenase-digested lung cells revealed a transient, early reduction in SiglecF hi CD11b low CD64 hi CD11c hi macrophages, countered by the sequential accumulation of SiglecF lo CD11b + CD64 2 CD11c 2 CCR2 + Ly6C + immature macrophages (3 d), Ly6G + neutrophils (7 d), and SiglecF hi CD11b hi CD11c lo eosinophils (2 wk). By mRNA analysis, BALF cells demonstrated a time-dependent phenotypic shift from a proinflammatory (3 d) to an anti-inflammatory/profibrotic activation state, along with serial elaboration of monocyte and eosinophil recruitment factors. The i.v. administration of clodronate effectively reduced total BALF cell numbers, CCR2 + immature macrophages, and eosinophil influx while improving survival. In contrast, resident macrophage depletion from the intratracheal delivery of clodronate liposomes enhanced Sftpc I73T-induced mortality. These results using Sftpc I73T mice provide a detailed ontogeny for AE-IPF driven by alveolar epithelial dysfunction that induces a polycellular inflammation initiated by the early influx of proinflammatory CCR2 + Ly6C hi immature macrophages.

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

“…These data support augmentation of TGFβ/ Smad signaling as an important intracellular defect contributing to the pathogenesis of IPF-like lung disease in conditional Nedd4-2 −/− mice. Third, based on previous reports that demonstrated a role of SP-C in familial forms of IPF 43 and recent Sftpc-based mouse models further supporting this notion 40,44 , we determined the role of Nedd4-2 deficiency on proSP-C trafficking. Our data support a role of Nedd4-2 in cellular SP-C trafficking in vivo, but genetic deletion of Sftpc did neither ameliorate (e.g., due to the deletion of a potentially toxic misprocessed proSP-C), nor aggravate (e.g., due to complete loss of SP-C) pulmonary fibrosis in conditional Nedd4-2 −/− mice (Fig.…”

<em>SFTPC</em> genetic polymorphisms are associated with tuberculosis susceptibility and clinical phenotype in a Western Chinese Han population

“…Changes in the alveolar lining fluid, including decreased binding ability of SFTPA and SFTPD to Mycobacterium tuberculosis , may increase TB susceptibility ( 29 ). It was reported that SFTPC is a hydrophobic membrane protein and serves a significant role in surfactant function ( 5 ), and mutations in SFTPC may modulate recruitment and activation of key myeloid cell populations in interstitial lung disease ( 30 ). However, there is very little data supporting the effects of SFTPC genetic polymorphisms on predisposition to and the clinical phenotype for TB, which is highly prevalent in China.…”

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

“…For example, a mutation in the MUC5B promoter associated with fibrosis results in enhanced expression of an abundant mucin secreted by lung epithelial cells (25). A mutation in SFTPC, the expression of which is restricted to alveolar type II cells, encodes a misfolded protein and expression of this mutant in alveolar type II cells from mice is sufficient to induce spontaneous pulmonary fibrosis (20,21,24). Loss of function in genes associated with the Hermansky-Pudlak syndrome disrupt intracellular protein transport and investigators have localized the effect of these mutants to the lung epithelium in animal models (22,23,63).…”

“…We and others have suggested that proteostatic stress induced by genetic mutations or environmental agents that drive fibrosis leads to the recruitment of profibrotic, monocyte-derived alveolar macrophages to the lung (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). We have shown that these monocyte-derived alveolar macrophages are maintained by autocrine or paracrine signaling via M-CSF/M-CSFR and localized specifically to regions of epithelial injury in close proximity to fibroblasts, inducing their activation, proliferation and secretion of matrix proteins (18).…”