title: Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via Gβγ/PKC/ERK1/2 pathway and heterologous receptor desensitization.
abstract: The niacin receptor HCA2 is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis. We previously reported that HCA2 in A431 epithelial cells transduced Gβγ-protein kinase C- and Gβγ-metalloproteinase/EGFR-dependent MAPK/ERK signaling cascades. Here, we investigated the role of HCA2 in macrophage-mediated inflammation and the underlying mechanisms. We found that proinflammatory stimulants LPS, IL-6 and IL-1β up-regulated the expression of HCA2 on macrophages. Niacin significantly inhibited macrophage chemotaxis in response to chemoattractants fMLF and CCL2 by disrupting polarized distribution of F-actin and Gβ protein. Niacin showed a selected additive effect on chemoattractant-induced activation of ERK1/2, JNK and PI3K pathways, but only the MEK inhibitor UO126 reduced niacin-mediated inhibition of macrophage chemotaxis, while activation of ERK1/2 by EGF alone did not inhibit fMLF-mediated migration of HEK293T cells co-expressing HCA2 and fMLF receptor FPR1. In addition, niacin induced heterologous desensitization and internalization of FPR1. Furthermore, niacin rescued mice from septic shock by diminishing inflammatory symptoms and the effect was abrogated in HCA2-/-mice. These results suggest that Gβγ/PKC-dependent ERK1/2 activation and heterologous desensitization of chemoattractant receptors are involved in the inhibition of chemoattractant-induced migration of macrophages by niacin. Thus, HCA2 plays a critical role in host protection against pro-inflammatory insults.
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lai
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Ye
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.
authors.forename: Wanghua
authors.initials: W
authors.lastname: Gong
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Lili
authors.initials: L
authors.lastname: Jin
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.|Xuzhou Yes Biotech Laboratories Ltd. Xuzhou, Jiangsu, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.|Department of Spine Surgery, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Mingyong
authors.initials: M
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Zhejiang University, Yu Hang Tang Load 388, Hangzhou, PR China.
authors.forename: Naiming
authors.initials: N
authors.lastname: Zhou
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D004705:Endocytosis; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009525:Niacin / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000199:Actins; D018932:Chemokine CCL2; D002630:Chemotactic Factors; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C473652:Hcar2 protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C