AhR–ROR‐γt complex is a therapeutic target for MAP4K3/GLK ^high IL‐17A ^high subpopulation of systemic lupus erythematosus

Abstract

ABSTRACT The cytokine IL‐17A plays critical roles in the pathogenesis of autoimmune diseases. The frequencies of MAP kinase kinase kinase kinase 3 [also named germinal center kinase–like kinase (GLK)]‐overexpressing T cells are correlated with disease severity of systemic lupus erythematosus (SLE). T‐cell–specific GLK‐transgenic mice develop spontaneous autoimmune responses through IL‐17A. GLK signaling selectively stimulates IL‐17A production in murine T cells through inducing aryl hydrocarbon receptor (AhR)–retinoic acid receptor–related orphan nuclear receptor‐³t (ROR‐³t) complex formation. Here, we investigated whether GLK‐induced AhR–ROR‐³t complex in T cells is a therapeutic target for human SLE. The population of GLK + IL‐17A + T cells was enhanced in the peripheral blood from patients with SLE compared with that of healthy controls using flow cytometry. The receiver operating characteristic curve analysis showed that increased GLK + IL‐17A + T‐cell population in peripheral blood reflected an active stage of SLE. In addition, peripheral blood T cells from patients with SLE displayed induction of ROR‐³t phosphorylation and the AhR‐ROR‐³t (and AhR–phosphorylated ROR‐³t) complex. Moreover, we identified a small‐molecule inhibitor, verteporfin, that inhibited GLK kinase activity and AhR–ROR‐³t interaction. The small‐molecule inhibitor verteporfin suppressed the disease severity in autoimmune mouse models and IL‐17A production in T cells from patients with SLE. Collectively, the GLK‐induced AhR‐ROR‐³t (and AhR–phosphorylated ROR‐³t) complex is a therapeutic target for the GLK high IL‐17A high subpopulation of human patients with SLE.—Chuang, H.‐C, Chen, Y.‐M., Chen, M.‐H., Hung, W.‐T., Yang, H.‐Y., Tseng, Y.‐H., Tan, T.‐H. AhR‐ROR‐³t complex is a therapeutic target for MAP4K3/GLK high IL‐17A high subpopulation of systemic lupus erythematosus. FA8EB J. 33, 11469–11480 (2019). www.fasebj.org