Extracellular

ATP activates the ATP-gated P2X7 receptor (P2X7R), which acts as a cation channel to rapidly induce potent K+ efflux and a complete collapse of normal ionic gradients 32. P2X7R activation also recruits pannexin-1 which mediates the formation of a pore that has been implicated in inflammasome activation 33. However, the concentration of ATP that is required for activation of the NLRP3 inflammasome in vitro far exceeds that found physiologically in the extracellular milieu. Thus, the relevance of the ATP-mediated pathway for inflammasome activation in vivo is unclear. Several pathogenic microorganisms including certain viruses, fungi and bacteria induce the activation of the NLRP3 inflammasome. For Enzalutamide example, NLRP3 regulates IL-1β production in response to influenza A, Sendai virus and vaccinia virus Ankara 34–38. In the case of influenza A virus, Akt inhibitor dsRNA production has been suggested to mediate inflammasome activation, although this remains controversial 34, 39, 40. One possibility is that dsRNA primes the NLRP3 inflammasome 29, 30. The importance of NLRP3 in host

defense against influenza A virus is also unclear because conflicting findings have been observed regarding its role in the control of viral burden, lung pathology and adaptive immune responses 34–36. The NLRP3 inflammasome is also critical for the regulation of IL-1β in response to the fungus Candida albicans41, 42. Importantly, the

NLRP3 inflammasome regulates fungal burden and survival in mice infected with C. albicans, which may be explained Tolmetin through IL-1β production and IL-1R signaling 41, 42. How fungal infection leads to inflammasome activation is unclear, but Syk, a tyrosine kinase acting downstream of multiple ITAM-coupled fungal PRR, was found to be important in both pro-IL-1β induction and caspase-1 activation 42. Caspase-1 activation was impaired in LPS-stimulated macrophages infected with the C. albicans, suggesting that Syk can direct the activation of NLRP3 independently of priming. One possibility is that Syk mediates ROS production 42 to induce inflammasome activation. Clearly more work is needed to understand the link between Syk and the activation of the NLRP3 inflammasome. The role of the NLRP3 inflammasome in the host defense response against Plasmodium berghei, a mouse model of malaria induced by Plasmodium falciparum, is controversial. β-hematin, a synthetic compound of hemozoin, a polymer resulting from the degradation of erythrocyte hemoglobin by the parasite, induces caspase-1 activation and IL-1β production through NLRP3 43–45. β-hematin activation of the NLRP3-inflammasome may involve the tyrosine kinases Syk and Lyn 43. Interestingly, NLRP3-deficient mice show mild protection against plasmodium infection when compared to WT mice 44, 45.