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In our earlier study, we showed that Leishmania donovani\u2013induced IL-33 destabilizes host cytokine dynamics by downregulating TNF-\u03b1 and IL-12 and ensures intramacrophage parasite survival. Another pertinent host favorable proinflammatory cytokine is Il-1\u03b2, maturation of which depends on the activation of NLRP3 inflammasome complex. Our present study highlights that independent neutralization of IL-33 and its receptor ST2, resulted in elevated levels of NLRP3 both at messenger RNA and protein levels, along with increased levels of mature IL-1\u03b2. Reduced NLRP3 expression during infection was correlated with decreased protein levels of p65, the major subunit of NF-\u03baB transcription factor complex. An unaltered transcript level of p65 in infected macrophages along with reduced protein expression suggested that post-translational modification and ubiquitination-mediated p65 degradation in the presence of IL-33 was found to be driven by the ubiquitin ligase SOCS1. Administration of IL-33\u2013neutralizing antibody in infected mice resulted in enhanced expression of both p65 and NLRP3, along with increased production of TNF-\u03b1, IL-12, and IL-1\u03b2, suggesting that IL-33 regulates these cytokines through a shared intermediary, p65. Neutralizing IL-33 during infection led to a reduction in SOCS1 expression, and SOCS1 knockdown by targeted short hairpin RNA in infected mice restores p65 levels, reactivates NLRP3 expressions, and reduces parasite burden in the visceral organs. This study highlights the IL-33\/SOCS1 pathway as a potential target for host-directed therapeutic strategies aimed at restoring protective immunity during chronic leishmaniasis.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag246","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:03:39Z","timestamp":1789549419000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Leishmania<\/i>\n                    inhibits NLRP3 expression through IL-33\/ST2 signaling driven SOCS1-mediated p65 degradation"],"prefix":"10.1093","volume":"215","author":[{"given":"Souravi","family":"Roy","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Calcutta , Kolkata,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayumi","family":"Mandal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Calcutta , Kolkata,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhurima","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Indian Institute of Science Education and Research , Bhopal,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha","family":"Madbhagat","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Indian Institute of Science Education and Research , Bhopal,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit","family":"Chande","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Indian Institute of Science Education and Research , 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