Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma

Liljevald, Maria; Rehnberg, Maria; Söderberg, Magnus; Ramnegård, Marie; Börjesson, Johan; Luciani, Donatella; Krutrök, Nina; Brändén, Lena; Johansson, Camilla; Xu, Xiufeng; Bjursell, Mikael; Sjögren, Anita; Hornberg, Jorrit J.; Andersson, Ulf; Kis, Dávid; Jirholt, Johan

doi:10.1016/j.autrev.2016.07.036

Cited by 52 publications

(39 citation statements)

References 43 publications

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“…Recently, it was reported that induction of Rorc deficiency in adult mice also leads to the development of thymic lymphoblastic lymphoma, similar to the thymic T cell lymphoma found in constitutive Rorc -/-mice and within a similar time frame (16).…”

Section: Rorc Physiological Roles Have Been Identified In Rorc-deficimentioning

confidence: 56%

See 1 more Smart Citation

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

Guntermann

Piaia

Hamel³

et al. 2017

JCI Insight

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Section: Rorc Physiological Roles Have Been Identified In Rorc-deficimentioning

confidence: 56%

“…Bcl2l1 mRNA expression was also significantly reduced in thymi of adult inducible Rorc -/-mice (16). qPCR analysis of mouse thymocytes revealed that 10 μM of cpd 1 or cpd 2 suppressed Bcl2l1 mRNA expression levels following 3-and 6-hour incubation ( Figure 7C).…”

Section: Resultsmentioning

confidence: 86%

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

Guntermann

Piaia

Hamel³

et al. 2017

JCI Insight

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“…Moreover, adult ROR-γt–deficient mice develop lymphoblastic lymphoma (30). Similarly, AhR regulates different immune responses through activating other AhR-regulated genes.…”

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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“…As a note of caution, mice in which Rorc deficiency was induced when the animals had already reached the adult stage, developed thymic lymphoblastic lymphoma similarly to what had been observed for constitutive Rorc −/− mice [132]. Moreover, patients with bi-allelic RORC mutations presented immunological alterations similar to the nullizygous mice, including loss of axillary and cervical lymph nodes, lack of iNKT and LTi cells, reduced thymus size and absence of IL-17A/F-producing T cells, ultimately resulting in impaired immune response to Mycobacterium and Candida [133].…”

Section: Targeting Transcription Factors: the New Frontier?mentioning

confidence: 99%

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Gadina

Gazaniga

Vian

et al. 2017

Journal of Autoimmunity

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Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

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Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma

Cited by 52 publications

References 43 publications

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

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

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

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

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Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma

Cited by 52 publications

References 43 publications

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

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

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

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

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Product

Resources

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