title: Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis.
abstract: Opportunistic lung infection and inflammation is a hallmark of chronic recreational/clinical use of morphine. We show that early induction of IL17 from the bronchial epithelium, following pathogenic encounter is a protective response, which contributes to pathogenic clearance and currently attributed to TLR2 activation in immune cells. Concurrent activation of TLR2 and IL17R in bronchial epithelium results in the sequestration of MyD88 (TLR2 adapter) by Act1/CIKS (IL17R adapter), thereby turning off TLR2 signaling to restore homeostasis. Morphine inhibits the early IL17 release and interaction between Act1 and MyD88, leading to decreased pathogenic clearance and sustained inflammation. Hence, we propose that therapeutically targeting either TLR2 or IL17 in bronchial epithelia, in the context of morphine, can restore inflammatory homeostasis.
authors.affiliation: Surgery, Basic and Translational Research, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, USA.
authors.forename: Santanu
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Surgery, Basic and Translational Research, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Ninkovic
authors.affiliation: Pharmacology, University of Minnesota, 321 Church St SE, Minneapolis, MN, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Meng
authors.affiliation: Surgery, Basic and Translational Research, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, USA.
authors.forename: Umakant
authors.initials: U
authors.lastname: Sharma
authors.affiliation: Surgery, Basic and Translational Research, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Surgery, Basic and Translational Research, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Charboneau
authors.affiliation: Surgery, Basic and Translational Research, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, USA.|Pharmacology, University of Minnesota, 321 Church St SE, Minneapolis, MN, USA.
authors.forename: Sabita
authors.initials: S
authors.lastname: Roy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D011008:Pneumococcal Infections / Q000209:etiology / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053722:Receptors, Interleukin-17; D017450:Receptors, Opioid, mu; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C515963:Traf3ip2 protein, mouse; D009020:Morphine