Pulmonary surfactant protein A regulates TLR expression and activity in human macrophages.
The pulmonary innate immune system responds to various airborne microbes. Although its specificity is broad and based on the recognition of pathogen-associated molecular patterns, it is uniquely regulated to limit inflammation and thereby prevent damage to the gas-exchanging alveoli. Macrophages, critical cell determinants of this system, recognize microbes through pattern recognition receptors such as TLRs, which typically mediate proinflammatory responses. The lung collectin, surfactant protein A (SP-A), has emerged as an important innate immune determinant that regulates microbe-macrophage interactions in this environment. In this study, we report the basal and SP-A-induced transcriptional and posttranslational regulation of TLR2 and TLR4 expression during the differentiation of primary human monocytes into macrophages. Despite SP-A's ability to up-regulate TLR2 expression on human macrophages, it dampens TLR2 and TLR4 signaling in these cells. SP-A decreases the phosphorylation of IkappaBalpha, a key regulator of NF-kappaB activity, and nuclear translocation of p65 which result in diminished TNF-alpha secretion in response to TLR ligands. SP-A also reduces the phosphorylation of TLR signaling proteins upstream of NF-kappaB, including members of the MAPK family. Finally, we report for the first time that SP-A decreases the phosphorylation of Akt, a major cell regulator of NF-kappaB and potentially MAPKs. These data identify a critical role for SP-A in modulating the lung inflammatory response by regulating macrophage TLR activity.
Center for Microbial Interface Biology, Ohio State University, Columbus, OH 43210, USA.
Lisa N
LN
Henning
Abul K
AK
Azad
Kishore V L
KV
Parsa
Joy E
JE
Crowther
Susheela
S
Tridandapani
Larry S
LS
Schlesinger
D000328:Adult; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018448:Models, Immunological; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D037662:Pulmonary Surfactant-Associated Protein A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D037662:Pulmonary Surfactant-Associated Protein A; D012333:RNA, Messenger; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha