P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis

Journal of Leukocyte Biology

Sabine Schneiter²  Simona Deplano²  Luigi Franchi³  Gurjeet Bhangal²  Robert J. Unwin¹  H. Terence Cook⁴  Ryan Russell²  Charles D. Pusey²  Frederick W. K. Tam, and²  Jacques Behmoaras ,⁴ 

[1]University College London Centre for Nephrology, University College London Medical School, Royal Free Campus and Hospital, London, United Kingdom  Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital, London, United Kingdom

[2]Renal Section and  Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital, London, United Kingdom

[3]Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA

[4] Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital, London, United Kingdom

关键词: WKY rat;    IL-1β;    caspase-1;    IL-18;    glomeruli;   

DOI  :  10.1189/jlb.0612284

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

P2RX7, a mediator of IL-1β and IL-18 processing and release, is a ligand-gated cation channel that is expressed by macrophages. In experimental Crgn, P2RX7 deficiency attenuates renal injury, but the underlying mechanism is unknown. Here, we show that P2RX7 levels and the expression of several genes belonging to the Nlrp3-inflammasome pathway are up-regulated in the macrophages of the WKY rat, a strain uniquely susceptible to macrophage-dependent NTN. Importantly, following P2RX7 activation, WKY BMDMs produce markedly increased levels of active caspase-1, IL-1β, and IL-18 when compared with the NTN-resistant LEW rat BMDMs. P2RX7 and active IL-1β, IL-18, and caspase-1 protein levels were markedly increased in the WKY nephritic glomeruli 4 days following induction of NTN, and the use of a P2RX7 antagonist reduced the levels of secreted active IL-1β. Interestingly, the post-translational control of P2RX7-mediated inflammasome activation is under the genetic regulation of two previously identified Crgn quantitative trait loci in the BMDMs and nephritic glomeruli of the WKY rat. In conclusion, we propose a novel mechanism, whereby genetically determined P2RX7 levels in macrophages regulate Nlrp3-inflammasome activation and susceptibility to Crgn.

【 授权许可】

Unknown