Metabolic danger signals, uric acid and ATP, mediate inflammatory cross‐talk between hepatocytes and immune cells in alcoholic liver disease

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: inflammasome;    NLRP3;    sterile inflammatory response;    DAMPs;    liver inflammation;   

DOI  :  10.1189/jlb.3AB1214-590R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

InflammationdefinestheprogressionofALDfromreversibletoadvancedstages.TranslocationofbacterialLPStotheliverfromthegutisnecessaryforalcohol‐inducedliverinflammation.However,itisnotknownwhetherendogenous,metabolicdangersignalsarerequiredforinflammationinALD.UricacidandATP,2majorproinflammatorydangersignals,wereevaluatedintheserumofhumanvolunteersexposedtoasingledoseofethanolorinsupernatantsofprimaryhumanhepatocytesexposedtoethanol.InvitrostudieswereusedtoevaluatetheroleofuricacidandATPininflammatorycross‐talkbetweenhepatocytesandimmunecells.ThesignificanceofsignalingdownstreamofuricacidandATPintheliverwasevaluatedinNLRP3‐deficientmicefedaLieber‐DeCarliethanoldiet.ExposureofhealthyhumanvolunteerstoasingledoseofethanolresultedinincreasedserumlevelsofuricacidandATP.Invitro,weidentifiedhepatocytesasasignificantsourceoftheseendogenousinflammatorysignals.UricacidandATPmediatedaparacrineinflammatorycross‐talkbetweendamagedhepatocytesandimmunecellsandsignificantlyincreasedtheexpressionofLPS‐induciblecytokines,IL‐1βandTNF‐α,byimmunecells.DeficiencyofNLRP3,aligand‐sensingcomponentoftheinflammasomerecognizinguricacidandATP,preventedthedevelopmentofalcohol‐inducedliverinflammationinmiceandsignificantlyamelioratedliverdamageandsteatosis.Endogenousmetabolicdangersignals,uricacid,andATPareinvolvedininflammatorycross‐talkbetweenhepatocytesandimmunecellsandplayacrucialroleinalcohol‐inducedliverinflammation...

【 授权许可】

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