The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation.
IL-25 initiates, promotes, and augments Th2 immune responses. In this study, we report that Act1, a key component in IL-17-mediated signaling, is an essential signaling molecule for IL-25 signaling. Although Act1-deficient mice showed reduced expression of KC (CXCL1) and neutrophil recruitment to the airway compared with wild-type mice in response to IL-17 stimulation, Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1 (CCL11), and pulmonary eosinophilia. Using a mouse model of allergic pulmonary inflammation, we observed diminished Th2 responses and lung inflammation in Act1-deficient mice compared with wild-type mice. Importantly, Act1 deficiency in epithelial cells reduced the phenotype of allergic pulmonary inflammation due to loss of IL-17-induced neutrophilia and IL-25-induced eosinophilia, respectively. These results demonstrate the essential role of epithelial-derived Act1 in allergic pulmonary inflammation through the distinct impact of the IL-17R-Act1 and IL-25R-Act1 axes. Such findings are crucial for the understanding of pathobiology of atopic diseases, including allergic asthma, which identifies Act1 as a potential therapeutic target.
Swaidani
Shadi
S
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Bulek
Katarzyna
K
Kang
Zizhen
Z
Liu
Caini
C
Lu
Yi
Y
Yin
Weiguo
W
Aronica
Mark
M
Li
Xiaoxia
X
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D004802:Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D020381:Interleukin-17 / Q000008:administration & dosage / Q000502:physiology*; D007378:Interleukins / Q000008:administration & dosage / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D018836:Inflammation Mediators; D020381:Interleukin-17; D007378:Interleukins; C442281:Mydgf protein, mouse; C515963:Traf3ip2 protein, mouse