GITR expressed on macrophages functions as an inflammatory amplifier by promoting NLRP3 inflammasome activation

Abstract

Abstract Glucocorticoid-induced tumor necrosis factor receptor (GITR) is an important co-stimulatory molecule on lymphocytes, however, its role on innate immunity and inflammatory response remains unclear. Our in vivo and in vitro data showed that bacterial infection up-regulated GITR expression in mouse macrophages. Treatment with agonistic anti-GITR Ab (DTA-1) enhanced, while knockout of GITR reduced the macrophage pyroptosis after bacterial infection. Furthermore, ELISA, Western blot and immune-fluorescence staining data indicated that GITR promoted NLRP3 inflammasome activation by inducing NLRP3 deubiquitination and ASC oligomerization, without affecting the priming stage. More importantly, we found that GITR expression was enhanced on peripheral monocytes/macrophages of sepsis patients vs healthy donors. Using cecal ligation and puncture (CLP) model of sepsis, we demonstrated that GITR triggered NLRP3 inflammasome activation to exacerbate disease progression, while this effect was reversed by treatment with specific inhibitor for NLRP3 or Caspase-1. Overall, our study demonstrated that GITR expressed on macrophages functions as an inflammatory amplifier by promoting NLRP3 inflammasome activation. These findings give a better understanding of GITR in innate immune response, which may also provide potential therapeutic targets of infectious and inflammatory diseases.