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Pulmonary Surfactant Protein A Regulates TLR Expression and Activity in Human Macrophages¹

Lisa N. Henning^*,, Abul K. Azad^*,,¶, Kishore V. L. Parsa^*,, Joy E. Crowther^*, Susheela Tridandapani^*,,¶ and Larry S. Schlesinger^2,*,,,

^* Center for Microbial Interface Biology, Division of Infectious Diseases, and Department of Medicine, and Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State Biochemistry Program and ^¶ Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210

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 IB, a key regulator of NF-B activity, and nuclear translocation of p65 which result in diminished TNF- secretion in response to TLR ligands. SP-A also reduces the phosphorylation of TLR signaling proteins upstream of NF-B, 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-B and potentially MAPKs. These data identify a critical role for SP-A in modulating the lung inflammatory response by regulating macrophage TLR activity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI059639 (to L.S.S.).

² Address correspondence and reprint requests to Dr. Larry S. Schlesinger, Department of Medicine, Division of Infectious Diseases, Center for Microbial Interface Biology, Ohio State University, 460 West 12th Avenue, Biomedical Research Tower, Room 1004, Columbus, OH 43210. E-mail address: larry.schlesinger{at}osumc.edu

³ Abbreviations used in this paper: AM, alveolar macrophage; MDM, monocyte-derived macrophage; MR, mannose receptor; SP-A, surfactant protein A; Pam₃Cys, Pam₃Cys-Ser-(Lys)₄ hydrochloride; PRR, pattern recognition receptor; BAL, bronchoalveolar lavage; APP, alveolar proteinosis patient; MFI, mean fluorescence intensity; RCN, relative copy number; Ct, cycle threshold; SR-A, scavenger receptor A.