Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

Guntermann, Christine; Piaia, Alessandro; Hamel, Marie-Laure; Theil, Diethilde; Rubic-Schneider, Tina; Río-Espínola, Alberto Del; Dong, Linda M.; Billich, Andreas; Kaupmann, Klemens; Dawson, Janet; Hoegenauer, Klemens; Orain, David; Hintermann, Samuel; Stringer, Rowan; Patel, Dhavalkumar D.; Doelemeyer, Arno; Deurinck, Mark; Schumann, Johann

doi:10.1172/jci.insight.91127

Cited by 52 publications

(62 citation statements)

References 33 publications

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“…ROR-γt inhibitors have been considered for treatment of autoimmune diseases and inflammation-associated diseases; however, ROR-γt inhibitors also induce side effects in animal studies due to the impairment of thymocyte development and dysregulation of other ROR-γt–regulated genes (28, 29). Moreover, adult ROR-γt–deficient mice develop lymphoblastic lymphoma (30).…”

Section: Discussionmentioning

confidence: 99%

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

Chuang

Chen

et al. 2019

FASEB j.

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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

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Section: Discussionmentioning

confidence: 99%

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

Chuang

Chen

et al. 2019

FASEB j.

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“…Given the essential function of RORgt in Th17 cells, pharmaceutical and academic scientists are developing RORgt inhibitors for treatment of Th17dependent autoimmunity (6,8,9,23,24). Unfortunately, such RORgt inhibitors can induce thymic lymphoma as a result of inhibition of RORgt in thymocyte development (25). Although SRC3 is required for Th17 differentiation, it is not essential for regulating thymocyte development (25,26); therefore, drugs that specifically disrupt the interaction between RORgt and SRC3 are expected to inhibit Th17-mediated pathological immunity without causing lymphoma by interference of thymocyte development.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, such RORgt inhibitors can induce thymic lymphoma as a result of inhibition of RORgt in thymocyte development (25). Although SRC3 is required for Th17 differentiation, it is not essential for regulating thymocyte development (25,26); therefore, drugs that specifically disrupt the interaction between RORgt and SRC3 are expected to inhibit Th17-mediated pathological immunity without causing lymphoma by interference of thymocyte development. We showed that K313 of RORgt is critical for binding to SRC3, indicating that amino acids surrounding K313 can potentially be targeted to disrupt the RORgt-SRC3 interaction.…”

Section: Discussionmentioning

confidence: 99%

SRC3 Is a Cofactor for RORγt in Th17 Differentiation but Not Thymocyte Development

Zhang

et al. 2019

The Journal of Immunology

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SRC3, a highly conserved member of the steroid receptor coactivator (SRC) family, is recruited by transcription factors to regulate cellular function. Previously, we demonstrated that SRC1, another highly conserved member of the SRC family, interacts with RORgt to regulate Th17 differentiation. However, the relationship between SRC1 and SRC3 in the regulation of Th17 cell function remains unknown. In this study, we demonstrate that mouse SRC3 interacts with RORgt in Th17 cells but not in thymocytes. In addition, Src3 2/2 mice exhibited defective Th17 differentiation and induction of experimental autoimmune encephalomyelitis but normal thymocyte development. Furthermore, a K313 to arginine mutation of RORgt (RORgt-K313R), which disrupts the interaction of RORgt with SRC3 but not with SRC1, impairs Th17 differentiation but not thymocyte development. These data suggest that SRC3 works with SRC1 to regulate RORgt-dependent Th17 differentiation but is not essential for RORgt-dependent thymocyte development.

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“…Figure 2) formed by M365,V 376, L400, F401, and S404. [18] The structure of 5 at 1.70 resolution using the RORgt[ 264-499] construct shows that the chlorine atomo f5 makes as trong halogen bond with OG-S404( 2.9 )i nt he backpocket and induces subtle structural changes of S404, with respect to 4 ( Figure 6). The terminal cyclopentyl group would clash with W317 if helix 12 is in the agonist position.…”

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confidence: 99%

Structural States of RORγt: X‐ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds

et al. 2017

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The T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-γ (RORγt) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORγt inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORγt agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co-crystallization with a co-activator peptide and helix 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORγt modulators.

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Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

Cited by 52 publications

References 33 publications

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

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

SRC3 Is a Cofactor for RORγt in Th17 Differentiation but Not Thymocyte Development

Structural States of RORγt: X‐ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds

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Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

Cited by 52 publications

References 33 publications

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

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

SRC3 Is a Cofactor for RORγt in Th17 Differentiation but Not Thymocyte Development

Structural States of RORγt: X‐ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds

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

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