Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12

Abstract

Surfactant protein D (SP-D) and CD14 are important innate immune defense molecules that mediate clearance of pathogens and apoptotic cells from the lung. To test whether CD14 expression and function were influenced by SP-D, the surface expression of CD14 was assessed on alveolar macrophages from SP-D−/− mice. CD14 was reduced on alveolar macrophages from SP-D−/− mice and was associated with reduced uptake of LPS and decreased production of TNF-α after LPS stimulation. CD14 is proteolytically cleaved from the cell surface to form a soluble peptide. Soluble CD14 (sCD14) was increased in the bronchoalveolar lavage fluid from SP-D−/− mice. Because matrix metalloproteinase (MMP)-9 and -12 activities were increased in the lungs of SP-D−/− mice, the role of these metalloproteases in the production of sCD14 was assessed. sCD14 was decreased in both MMP9−/−/SP-D−/− and MMP12−/−/SP-D−/− mice demonstrating MMP-9 and MMP-12 contribute to proteolytic shedding of CD14. The increased sCD14 seen in SP-D−/− mice was dependent upon the activation of MMP-12 via an MMP-9-dependent mechanism. Supporting this observation, MMP-12 caused the release of sCD14 from RAW 264.7 cells in vitro. In conclusion, SP-D influences innate host defense, in part, by regulating sCD14 in a process mediated by MMP-9 and MMP-12.