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1.
Immunity ; 56(9): 2006-2020.e6, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37473759

RESUMO

Anti-interleukin-17 (IL-17) therapy has been used in various autoimmune diseases. However, the efficacy is unexpectedly limited in several IL-17-associated diseases, and the mechanism of limited efficacy remains unclear. Here, we show that a molecular complex containing the adaptor molecule Act1 and tyrosine phosphatase SHP2 mediated autonomous IL-17R signaling that accelerated and sustained inflammation. SHP2, aberrantly augmented in various autoimmune diseases, was induced by IL-17A itself in astrocytes and keratinocytes, sustaining chemokine production even upon anti-IL-17 therapies. Mechanistically, SHP2 directly interacted with and dephosphorylated Act1, which replaced Act1-TRAF5 complexes and induced IL-17-independent activation of IL-17R signaling. Genetic or pharmacologic inactivation of SHP2, or blocking Act1-SHP2 interaction, paralyzed both IL-17-induced and IL-17-independent signaling and attenuated primary or relapsing experimental autoimmune encephalomyelitis. Therefore, Act1-SHP2 complexes mediate an alternative pathway for autonomous activation of IL-17R signaling, targeting which could be a therapeutic option for IL-17-related diseases in addition to current antibody therapies.


Assuntos
Encefalomielite Autoimune Experimental , Receptores de Interleucina-17 , Animais , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inflamação , Progressão da Doença
2.
Acta Pharmacol Sin ; 45(9): 1926-1936, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38744938

RESUMO

Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.


Assuntos
Diferenciação Celular , Cromonas , Plasmócitos , Proteínas Tirosina Quinases , Síndrome de Sjogren , Sulfonamidas , Animais , Síndrome de Sjogren/tratamento farmacológico , Feminino , Diferenciação Celular/efeitos dos fármacos , Camundongos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Plasmócitos/efeitos dos fármacos , Cromonas/farmacologia , Cromonas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Modelos Animais de Doenças , Humanos , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico
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