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Requirement of Gαi1 and Gαi3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response.
Bai, Jin-Yu; Li, Ya; Xue, Guan-Hua; Li, Ke-Ran; Zheng, Yu-Fan; Zhang, Zhi-Qing; Jiang, Qin; Liu, Yuan-Yuan; Zhou, Xiao-Zhong; Cao, Cong.
Afiliación
  • Bai JY; Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, China.
  • Li Y; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
  • Xue GH; The Central Lab, North District, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
  • Li KR; Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • Zheng YF; The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
  • Zhang ZQ; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
  • Jiang Q; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
  • Liu YY; The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
  • Zhou XZ; Clinical research & lab center, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
  • Cao C; Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, China.
Theranostics ; 11(10): 4894-4909, 2021.
Article en En | MEDLINE | ID: mdl-33754034
IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of Gαi1 and Gαi3 in M2 polarization using multiple genetic methods. Methods and Results: In MEFs and primary murine BMDMs, Gαi1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4Rα endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Following IL-4 stimulation, Gαi1/3 proteins associated with the intracellular domain of IL-4Rα and the APPL1 adaptor, to mediate IL-4Rα endosomal traffic and Gab1-Akt activation in BMDMs. In contrast, gene silencing of Gαi1/3 with shRNA or knockout resulted in BMDMs that were refractory to IL-4-induced M2 polarization. Conversely, Gαi1/3-overexpressed BMDMs displayed preferred M2 response with IL-4 stimulation. In primary human macrophages IL-4-induced Akt activation and Th2 genes expression were inhibited with Gαi1/3 silencing, but augmented with Gαi1/3 overexpression. In Gαi1/3 double knockout (DKO) mice, M2 polarization, by injection of IL-4 complex or chitin, was potently inhibited. Moreover, in a murine model of asthma, ovalbumin-induced airway inflammation and hyperresponsiveness were largely impaired in Gαi1/3 DKO mice. Conclusion: These findings highlight novel and essential roles for Gαi1/3 in regulating IL-4-induced signaling, macrophage M2 polarization and allergic asthma response.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hipersensibilidad Respiratoria / Asma / Interleucina-4 / Subunidades alfa de la Proteína de Unión al GTP Gi-Go / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Theranostics Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hipersensibilidad Respiratoria / Asma / Interleucina-4 / Subunidades alfa de la Proteína de Unión al GTP Gi-Go / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Theranostics Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia