title: Mer signaling increases the abundance of the transcription factor LXR to promote the resolution of acute sterile inflammation.
abstract: The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of immune cells to pathogens. We aimed to understand the function of Mer signaling in the resolution of sterile inflammation in experiments with a Mer-neutralizing antibody or with Mer-deficient (Mer-/-) mice in a model of sterile, zymosan-induced acute inflammation. We found that inhibition or deficiency of Mer enhanced local and systemic inflammatory responses. The exacerbated inflammatory responses induced by the lack of Mer signaling were associated with reduced abundance of the transcription factors liver X receptor α (LXRα) and LXRβ and decreased expression of their target genes in peritoneal macrophages, spleens, and lungs. Similarly, treatment of mice with a Mer/Fc fusion protein, which prevents the Mer ligand Gas6 (growth arrest-specific protein 6) from binding to Mer, exacerbated the inflammatory response and decreased the abundance of LXR. Coadministration of the LXR agonist T0901317 with the Mer-neutralizing antibody inhibited the aggravating effects of the antibody on inflammation in mice. In vitro exposure of RAW264.7 cells or primary peritoneal macrophages to Gas6 increased LXR abundance in an Akt-dependent manner. Thus, we have elucidated a previously uncharacterized pathway involved in the resolution of acute sterile inflammation: Enhanced Mer signaling during the recovery phase increases the abundance and activity of LXR to inactivate the inflammatory response in macrophages.
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-056, Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-056, Korea.
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Seo
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-056, Korea.
authors.forename: Young-So
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-056, Korea.
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-056, Korea.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-056, Korea. jihee@ewha.ac.kr.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
mesh_terms: D000208:Acute Disease; D000818:Animals; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015054:Zymosan / Q000633:toxicity; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D015054:Zymosan; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000605214:Nr1h3 protein, mouse; C490767:Mertk protein, mouse