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

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 GLKhighIL‐17Ahigh 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/GLKhighIL‐17Ahigh subpopulation of systemic lupus erythematosus. FA8EB J. 33, 11469–11480 (2019). http://www.fasebj.org

MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus

“…Consistently, GLK is overexpressed in the peripheral blood leukocytes (PBLs) of SLE patients; the activation of PKCθ and IKK are concomitantly induced in SLE PBLs compared to those of healthy controls [22] (Figure 2). The frequencies of GLK-overexpressing T cells, but not B cells, are increased in SLE patients, compared to those of healthy controls [9,22]. The GLK-overexpressing T cell population is correlated with the SLE disease activity index (SLEDAI) [9,22].…”

“…Inflammatory cytokines play an important role in the pathogenesis of autoimmune diseases. In particular, interleukin 17A (IL-17A) plays a critical role in SLE pathogenesis [4,5,6,7,8,9,10,11]. Several biologic agents have been used to treat autoimmune diseases [12,13,14,15,16,17]; however, the development of an effective therapeutic approach for SLE is very challenging due to the complexity and heterogeneity of the disease [4].…”

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

“…However, emerging evidence suggests that GLK regulates T-cell activation via IL-17A signaling [87]. Accordingly, the GLK inhibitor, Verteporfin, has been approved by FDA in macular degeneration of eyes [88] and may warrant exploration in cancer.…”

MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1

“…GLK also upregulates NF-kB signaling by activating PKC-q in T cells, leading to T-cell activation (28,29). GLK signaling in T cells specifically enhances IL17A transcription by inducing the AhR-RORgt complex (30,31). The increase of GLK protein levels in T cells is correlated with the disease severity of several human autoimmune diseases (28,(31)(32)(33).…”

“…GLK signaling in T cells specifically enhances IL17A transcription by inducing the AhR-RORgt complex (30,31). The increase of GLK protein levels in T cells is correlated with the disease severity of several human autoimmune diseases (28,(31)(32)(33). Moreover, GLK protein levels are increased in tissues of human lung cancer and hepatoma (34,35); GLK overexpression in the cancer tissue is correlated with cancer recurrence and poor recurrence-free survival rates (34,35).…”