Surfactant protein-D regulates soluble CD14 through matrix metalloproteinase-12.
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-alpha 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 MMP(9-/-)/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.
Senft
Albert P
AP
Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Korfhagen
Thomas R
TR
Whitsett
Jeffrey A
JA
Shapiro
Steven D
SD
LeVine
Ann Marie
AM
D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004247:DNA / Q000235:genetics; D004705:Endocytosis; D005260:Female; D007113:Immunity, Innate; D066298:In Vitro Techniques; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D004247:DNA; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12