Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2

作者：Gupta Anand Kumar; Ghosh Kuntal; Palit Shreyasi; Barua Jayita; Das Pijush K^*; Ukil Anindita^*

来源：The FASEB Journal, 2017, 31(11): 5087-5101.

DOI：10.1096/fj.201700407R

• IL-1 beta
• caspase-1
• NF-kappa B
• ROS

In visceral leishmaniasis, we found that the antileishmanial drug Amp B produces a higher level of IL-1 beta over the infected control. Moreover, administering anti-IL-1 beta antibody to infected Amp B-treated mice showed significantly less parasite clearance. Investigation revealed that Leishmania inhibits stimuli-induced expression of a multiprotein signaling platform, NLRP3 inflammasome, which in turn inhibits caspase-1 activation mediated maturation of IL-1 beta from its pro form. Attenuation of NLRP3 and pro-IL-1 beta in infection was found to result from decreased NF-kappa B activity. Transfecting infected cells with constitutively active NF-kappa B plasmid increased NLRP3 and pro-IL-1 beta expression but did not increase mature IL-1 beta, suggesting that IL-1 beta maturation requires a second signal, which was found to be reactive oxygen species (ROS). Decreased NF-kappa B was attributed to increased expression of A20, a negative regulator of NF-kappa B signaling. Silencing A20 in infected cells restored NLRP3 and pro-IL-1 beta expression, but also increased matured IL-1 beta, implying an NF-kappa B-independent A20-modulated IL-1 beta maturation. Macrophage ROS is primarily regulated by mitochondrial uncoupling protein 2 (UCP2), and UCP2-silencedinfected cells showed an increased IL-1 beta level. Shorthairpin RNA-mediated knockdown of A20 and UCP2 in infected mice independently documented decreased liver and spleen parasite burden and increased IL-1 beta production. These results suggest that Leishmania exploits A20 and UCP2 to impair inflammasome activation for disease propagation.-Gupta, A. K., Ghosh, K., Palit, S., Barua, J., Das, P. K., Ukil, A. Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2.

• 出版日期2017-11