title: Scavenger receptor A restrains T-cell activation and protects against concanavalin A-induced hepatic injury.
abstract: Negative feedback immune mechanisms are essential for maintenance of hepatic homeostasis and prevention of immune-mediated liver injury. We show here that scavenger receptor A (SRA/CD204), a pattern recognition molecule, is highly up-regulated in the livers of patients with autoimmune or viral hepatitis, and of mice during concanavalin A (Con A)-induced hepatitis (CIH). Strikingly, genetic SRA ablation strongly sensitizes mice to Con A-induced liver injury. SRA loss, increased mortality and liver pathology correlate with excessive production of IFN-γ and heightened activation of T cells. Increased liver expression of SRA primarily occurs in mobilized hepatic myeloid cells during CIH, including CD11b(+) Gr-1(+) cells. Mechanistic studies establish that SRA on these cells functions as a negative regulator limiting T-cell activity and cytokine production. SRA-mediated protection from CIH is further validated by adoptive transfer of SRA(+) hepatic mononuclear cells or administration of a lentivirus-expressing SRA, which effectively ameliorates Con A-induced hepatic injury. Also, CIH and clinical hepatitis are associated with increased levels of soluble SRA. This soluble SRA displays a direct T-cell inhibitory effect and is capable of mitigating Con A-induced liver pathology.
  
  
  CONCLUSIONS
  Our findings demonstrate an unexpected role of SRA in attenuation of Con A-induced, T-cell-mediated hepatic injury. We propose that SRA serves as an important negative feedback mechanism in liver immune homeostasis, and may be exploited for therapeutic treatment of inflammatory liver diseases.
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors: Daming
authors: D
authors: Zuo
authors: Xiaofei
authors: X
authors: Yu
authors: Chunqing
authors: C
authors: Guo
authors: Hongxia
authors: H
authors: Wang
authors: Jie
authors: J
authors: Qian
authors: Huanfa
authors: H
authors: Yi
authors: Xiao
authors: X
authors: Lu
authors: Zhi-Ping
authors: ZP
authors: Lv
authors: John R
authors: JR
authors: Subjeck
authors: Huiping
authors: H
authors: Zhou
authors: Arun J
authors: AJ
authors: Sanyal
authors: Zhengliang
authors: Z
authors: Chen
authors: Xiang-Yang
authors: XY
authors: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity*; D006520:Hepatitis, Animal / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D051117:Scavenger Receptors, Class A; D003208:Concanavalin A; D007371:Interferon-gamma