| First Author | Gupta AK | Year | 2017 |
| Journal | FASEB J | Volume | 31 |
| Issue | 11 | Pages | 5087-5101 |
| PubMed ID | 28765172 | Mgi Jnum | J:253385 |
| Mgi Id | MGI:6108492 | Doi | 10.1096/fj.201700407R |
| Citation | Gupta AK, et al. (2017) Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2. FASEB J 31(11):5087-5101 |
| abstractText | In visceral leishmaniasis, we found that the antileishmanial drug Amp B produces a higher level of IL-1beta over the infected control. Moreover, administering anti-IL-1beta 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-1beta from its pro form. Attenuation of NLRP3 and pro-IL-1beta in infection was found to result from decreased NF-kappaB activity. Transfecting infected cells with constitutively active NF-kappaB plasmid increased NLRP3 and pro-IL-1beta expression but did not increase mature IL-1beta, suggesting that IL-1beta maturation requires a second signal, which was found to be reactive oxygen species (ROS). Decreased NF-kappaB was attributed to increased expression of A20, a negative regulator of NF-kappaB signaling. Silencing A20 in infected cells restored NLRP3 and pro-IL-1beta expression, but also increased matured IL-1beta, implying an NF-kappaB-independent A20-modulated IL-1beta maturation. Macrophage ROS is primarily regulated by mitochondrial uncoupling protein 2 (UCP2), and UCP2-silenced infected cells showed an increased IL-1beta level. Short hairpin RNA-mediated knockdown of A20 and UCP2 in infected mice independently documented decreased liver and spleen parasite burden and increased IL-1beta 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. |
