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OSCAR is a receptor for surfactant protein D that activates TNF-? release from human CCR2+ inflammatory monocytes.

ABSTRACT: Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D-encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (OSCAR) within the SP-D collagenous domain. An OSCAR-Fc fusion protein specifically bound to the collagenous region of recombinant SP-D and captured native SP-D from human bronchoalveolar lavage. OSCAR localized in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we found OSCAR on the surface of interstitial lung and blood CCR2(+) inflammatory monocytes, which secreted TNF-? when exposed to SP-D in an OSCAR-dependent fashion. OSCAR and SP-D did not exclusively colocalize in lung, as they were also highly expressed in atherosclerotic plaques of human aorta, supporting a role for this interaction in atherosclerosis. Our results identify the OSCAR:SP-D interaction as a potential therapeutic target in chronic inflammatory diseases of the lung as well as other diseases involving tissue accumulation of SP-D, infiltration of inflammatory monocytes, and release of TNF-?.

SUBMITTER: Barrow AD

PROVIDER: S-EPMC4369396 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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OSCAR is a receptor for surfactant protein D that activates TNF-α release from human CCR2+ inflammatory monocytes.

Barrow Alexander D AD Palarasah Yaseelan Y Bugatti Mattia M Holehouse Alex S AS Byers Derek E DE Holtzman Michael J MJ Vermi William W Skjødt Karsten K Crouch Erika E Colonna Marco M

Journal of immunology (Baltimore, Md. : 1950) 20150225 7

Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D-encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (O ...[more]

PMID: 25716998

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Project description:Background P-glycoprotein (P-gp), encoded by the ABCB1 gene, actively pumps drugs and other xenobiotics from trophoblast cells back into the maternal circulation and thus acts as one of the most critical protectors of the fetus. The effect of tumor necrosis factor-α (TNF-α) on P-gp and molecule-transporting activity remains unknown. The goal of this study was to investigate the role of TNF-α in placental molecule-transporting activity and the underlies mechanisms. Methods Cultured human placental choriocarcinoma cell lines, Bewo, JEG-3 and JAR, were used in this study. Cultured cells were incubated with 5, 10 and 20 ng/mL of recombinant TNF-α (rTNF-α) for 24 h, respectively, for follow-up experiments. The dimer form and expression of activator protein-1 (AP-1) family members were detected using Western blot (WB) and chromatin immunoprecipitation (ChIP). mRNA and protein expression of ABCB1 were detected using reverse transcriptional quantitative polymerase chain reaction (RT-qPCR) and WB, respectively. Double luciferase labeling was used to verify the concentration of digoxin. Electromobility shift assay (EMSA) and ChIP were used to identify the binding ability of c-Jun to ABCB1 gene promoter. Proliferation and apoptosis of Bewo cells were determined using flow cytometry. Digoxin concentration were determined using dual luciferase labeling method. Results Administration of rTNF-α upregulated the expression of c-Jun but not JunB or JunD in a dose-dependent manner and promoted the binding of c-Jun to the ABCB1 promoter region in Bewo cells. rTNF-α also increased the uptake of two P-gp-specific substrates, Rh123 and DiOC2(3), a function reversed by the addition of SP600125 and SR11302. We also found that rTNF-α increased the efflux ratio of digoxin, an outcome that was reversed, as expected, by inhibiting c-Jun and P-gp binding activities. Furthermore, we identified that rTNF-α tightly regulates the molecule-transporting activity of P-gp by promoting the phosphorylation of c-Jun. Conclusions TNF-α activates P-gp to promote placental molecule-transporting activity by directly upregulating c-Jun expression and phosphorylation. These findings demonstrate the clinical significance of TNF-α in modulating the placental barrier, which plays an important role in protecting fetus against harmful drugs.

Dataset Information

OSCAR is a receptor for surfactant protein D that activates TNF-? release from human CCR2+ inflammatory monocytes.

Publications

OSCAR is a receptor for surfactant protein D that activates TNF-α release from human CCR2+ inflammatory monocytes.

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