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Our laboratory has demonstrated that an inhaled combination of a Toll-like receptor (TLR) 2\/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonias. We have previously shown that intact epithelial TLR signaling and generation of multisource epithelial reactive oxygen species (ROS) are required for inducible protection. Further investigating the mechanisms underlying this phenomenon of inducible resistance, reverse-phase protein array analysis demonstrated robust STAT3 (signal transducer and activator of transcription 3) phosphorylation following treatment of lung epithelial cells. We show here that Pam2ODN-induced STAT3 phosphorylation is IL-6\u2013independent. We further found that therapeutic epithelial STAT3 activation is required for inducible protection against Pseudomonas aeruginosa pneumonia. Additional studies showed that inhibiting epithelial dual oxidases or scavenging ROS significantly reduced the Pam2ODN induction of STAT3 phosphorylation, suggesting a proximal role for ROS in inducible STAT3 activation. Dissecting these mechanisms, we analyzed the contributions of redox-sensitive kinases and found that Pam2ODN activated epithelial growth factor receptor in an ROS-dependent manner that is required for therapeutically inducible STAT3 activation. Taken together, we demonstrate that epithelial STAT3 is imperative for Pam2ODN\u2019s function and describe a novel redox-based mechanism for its activation. These key mechanistic insights may facilitate strategies to leverage inducible epithelial resistance to protect susceptible patients during periods of peak vulnerability.<\/jats:p>","DOI":"10.1165\/rcmb.2022-0342oc","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T11:27:10Z","timestamp":1677238030000},"page":"679-688","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":13,"title":["Redox-Dependent Activation of Lung Epithelial STAT3 Is Required for Inducible Protection against Bacterial Pneumonia"],"prefix":"10.1093","volume":"68","author":[{"given":"Vikram V.","family":"Kulkarni","sequence":"first","affiliation":[{"name":"MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, Texas; and"},{"name":"Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, 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