PI3Kγ controls leukocyte recruitment, tissue injury, and lethality in a model of graft-versus-host disease in mice

Journal of Leukocyte Biology

BÃrbara M. Rezende¹  Rosa M. E. Arantes–¹  Tarcília A. Silva¹  Danielle G. Souza¹  Priscila T. T. Bernardes¹  Angélica T. Vieira¹  Érica L. M. Vieira¹  Marina G. M. Castor¹  Vanessa Pinho¹  Mauro M. Teixeira, and¹ 

[1] Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia,  Departamento de Fisiologia e Biofísica, Departamento de Morfologia, Departamento de Microbiologia, –Laboratório de Neuro-Imunopatologia Experimental, Departamento de Patologia, Instituto de Ciências Biológicas, Departamento Clínicas, Patologia e Cirurgia Odontológicas, Faculdade de Odontologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

关键词: inflammation;    cell signaling;    cell migration;   

DOI  :  10.1189/jlb.0810464

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

PI3Kγ is thought to mediate leukocyte migration to injured tissues and may be important in the pathogenesis of various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases. The present study evaluated the relevance of PI3Kγ in donor cells for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PI3Kγ−/− C57BL/6J mice to B6D2F1 mice, and mice that received PI3Kγ−/− cells showed reduced clinical signs of disease, bacterial translocation, tissue injury, and lethality rates. This was associated with reduced production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and reduced infiltration of CD8+, CD4+, and CD11c+ cells in the small intestine. Mechanistically, in addition to decreasing production of proinflammatory mediators, absence or pharmacological blockade of PI3Kγ was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PI3Kγ−/− leukocytes were transferred into WT mice. In conclusion, PI3Kγ plays a critical role in GVHD by mediating leukocyte influx and activation in tissues. PI3Kγ inhibitors may be useful in the treatment of GVHD in patients undergoing BMT.

【 授权许可】

Unknown