PMID- 28892097 OWN - NLM STAT- MEDLINE DCOM- 20171214 LR - 20230411 IS - 1530-0307 (Electronic) IS - 0023-6837 (Print) IS - 0023-6837 (Linking) VI - 97 IP - 12 DP - 2017 Dec TI - Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses. PG - 1471-1487 LID - 10.1038/labinvest.2017.92 [doi] AB - The Ah receptor (AHR) has been shown to exhibit both inflammatory and anti-inflammatory activity in a context-specific manner. In vivo macrophage-driven acute inflammation models were utilized here to test whether the selective Ah receptor modulator 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA360) would reduce inflammation. Exposure to SGA360 was capable of significantly inhibiting lipopolysaccharide (LPS)-mediated endotoxic shock in a mouse model, both in terms of lethality and attenuating inflammatory signaling in tissues. Topical exposure to SGA360 was also able to mitigate joint edema in a monosodium urate (MSU) crystal gout mouse model. Inhibition was dependent on the expression of the high-affinity allelic AHR variant in both acute inflammation models. Upon peritoneal MSU crystal exposure SGA360 pretreatment inhibited neutrophil and macrophage migration into the peritoneum. RNA-seq analysis revealed that SGA360 attenuated the expression of numerous inflammatory genes and genes known to be directly regulated by AHR in thioglycolate-elicited primary peritoneal macrophages treated with LPS. In addition, expression of the high-affinity allelic AHR variant in cultured macrophages was necessary for SGA360-mediated repression of inflammatory gene expression. Mechanistic studies revealed that SGA360 failed to induce nuclear translocation of the AHR and actually enhanced cytoplasmic localization. LPS treatment of macrophages enhanced the occupancy of the AHR and p65 to the Ptgs2 promoter, whereas SGA360 attenuated occupancy. AHR ligand activity was detected in peritoneal exudates isolated from MSU-treated mice, thus suggesting that the anti-inflammatory activity of SGA360 is mediated at least in part through AHR antagonism of endogenous agonist activity. These results underscore an important role of the AHR in participating in acute inflammatory signaling and warrants further investigations into possible clinical applications. FAU - Muku, Gulsum E AU - Muku GE AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. FAU - Lahoti, Tejas S AU - Lahoti TS AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. FAU - Murray, Iain A AU - Murray IA AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. FAU - Podolsky, Michael A AU - Podolsky MA AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. FAU - Smith, Kayla J AU - Smith KJ AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. FAU - Hubbard, Troy D AU - Hubbard TD AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. FAU - Kuzu, Guray AU - Kuzu G AD - Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA. FAU - Gowda, Krishne AU - Gowda K AD - Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA, USA. FAU - Amin, Shantu G AU - Amin SG AD - Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA, USA. FAU - Perdew, Gary H AU - Perdew GH AD - Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. LA - eng GR - R01 ES004869/ES/NIEHS NIH HHS/United States GR - R01 ES019964/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170911 PL - United States TA - Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology JID - 0376617 RN - 0 (Allyl Compounds) RN - 0 (Indazoles) RN - 0 (Lipopolysaccharides) RN - 0 (Receptors, Aryl Hydrocarbon) RN - 0 (SGA 360) SB - IM MH - Allyl Compounds/pharmacology MH - Animals MH - Cells, Cultured MH - Cytoplasm/*metabolism MH - Disease Models, Animal MH - Gout/metabolism MH - Indazoles/pharmacology MH - Inflammation/*metabolism MH - Lipopolysaccharides MH - *Macrophages, Peritoneal/drug effects/metabolism MH - Mice MH - Mice, Knockout MH - Receptors, Aryl Hydrocarbon/*metabolism PMC - PMC5711556 MID - NIHMS894394 COIS- DISCLOSURE/CONFLICT OF INTEREST The authors declare no conflict of interest. EDAT- 2017/09/12 06:00 MHDA- 2017/12/15 06:00 PMCR- 2018/03/11 CRDT- 2017/09/12 06:00 PHST- 2017/05/07 00:00 [received] PHST- 2017/07/12 00:00 [revised] PHST- 2017/07/18 00:00 [accepted] PHST- 2017/09/12 06:00 [pubmed] PHST- 2017/12/15 06:00 [medline] PHST- 2017/09/12 06:00 [entrez] PHST- 2018/03/11 00:00 [pmc-release] AID - S0023-6837(22)00749-8 [pii] AID - 10.1038/labinvest.2017.92 [doi] PST - ppublish SO - Lab Invest. 2017 Dec;97(12):1471-1487. doi: 10.1038/labinvest.2017.92. Epub 2017 Sep 11.