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Overproduction of mucin, the major component of mucus, plays a critical role in the pathogenesis of both OM and pneumonia. However, the molecular mechanisms underlying the tight regulation of mucin upregulation in the mucosal epithelium by S. pneumoniae infection remain largely unknown. In this study, we show that S. pneumoniae pneumolysin (PLY) activates AMP-activated protein kinase \u03b11 (AMPK\u03b11), the master regulator of energy homeostasis, which is required for S. pneumoniae\u2013induced mucin MUC5AC upregulation in vitro and in vivo. Moreover, we found that PLY activates AMPK\u03b11 via cholesterol-dependent membrane binding of PLY and subsequent activation of the Ca2+\u2013 Ca2+\/calmodulin-dependent kinase kinase \u03b2 (CaMKK\u03b2) and Cdc42\u2013mixed-lineage protein kinase 3 (MLK3) signaling axis in a TLR2\/4-independent manner. AMPK\u03b11 positively regulates PLY-induced MUC5AC expression via negative cross-talk with TLR2\/4-dependent activation of MAPK JNK, the negative regulator of MUC5AC expression. Moreover, pharmacological inhibition of AMPK\u03b11 suppressed MUC5AC induction in the S. pneumoniae\u2013induced OM mouse model, thereby demonstrating its therapeutic potential in suppressing mucus overproduction in OM. Taken together, our data unveil a novel mechanism by which negative cross-talk between TLR2\/4-independent activation of AMPK\u03b11 and TLR2\/4-dependent activation of JNK tightly regulates the S. pneumoniae PLY-induced host mucosal innate immune response.<\/jats:p>","DOI":"10.4049\/jimmunol.2100901","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T17:42:41Z","timestamp":1666287761000},"page":"1532-1544","source":"Crossref","is-referenced-by-count":5,"title":["Negative Cross-Talk between TLR2\/4-Independent AMPK\u03b11 and TLR2\/4-Dependent JNK Regulates <i>S. pneumoniae<\/i>\u2013Induced Mucosal Innate Immune Response"],"prefix":"10.1093","volume":"209","author":[{"given":"Shingo","family":"Matsuyama","sequence":"first","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7418-3805","authenticated-orcid":false,"given":"Kensei","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung-Cheol","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukihiro","family":"Tasaki","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Miyata","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haidong","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Shuto","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Kai","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5593-050X","authenticated-orcid":false,"given":"Jian-Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,10,15]]},"reference":[{"key":"2025021008352040100_r1","first-page":"62","article-title":"Recent advances in otitis media. 6. 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