Volume 13 Issue 6
Jun.  2023
Turn off MathJax
Article Contents
Jiuping Zeng, Mingxing Li, Qianyun Zhao, Meijuan Chen, Long Zhao, Shulin Wei, Huan Yang, Yueshui Zhao, Anqi Wang, Jing Shen, Fukuan Du, Yu Chen, Shuai Deng, Fang Wang, Zhuo Zhang, Zhi Li, Tiangang Wang, Shengpeng Wang, Zhangang Xiao, Xu Wu. Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 545-562. doi: 10.1016/j.jpha.2023.05.009
Citation: Jiuping Zeng, Mingxing Li, Qianyun Zhao, Meijuan Chen, Long Zhao, Shulin Wei, Huan Yang, Yueshui Zhao, Anqi Wang, Jing Shen, Fukuan Du, Yu Chen, Shuai Deng, Fang Wang, Zhuo Zhang, Zhi Li, Tiangang Wang, Shengpeng Wang, Zhangang Xiao, Xu Wu. Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 545-562. doi: 10.1016/j.jpha.2023.05.009

Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases

doi: 10.1016/j.jpha.2023.05.009
Funds:

This work was supported by the grants from the Sichuan Science and Technology Program, China (Grant Nos.: 2023NSFSC0614 and 2022YFS0624), Southwest Medical University Science and Technology Program, China (Grant No.: 2021ZKZD017), the Luzhou Science and Technology Program, China (Grant Nos.: 2022-YJY-127, 2022YFS0624-B1, 2022YFS0624-C1, and 2022YFS0624-B3), and the Open Research Project Program funded by the Science and Technology Development Fund (Grant No.: SKL-QRCM(UM)-2020-2022) and the State Key Laboratory of Quality Research in Chinese Medicine (University of Macau, Macao, China) (Grant No.: SKL-QRCM-OP21006).

  • Received Date: Feb. 10, 2023
  • Accepted Date: May 16, 2023
  • Rev Recd Date: May 05, 2023
  • Publish Date: May 20, 2023
  • As a ligand-dependent transcription factor, retinoid-associated orphan receptor γt (RORγt) that controls T helper (Th) 17 cell differentiation and interleukin (IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune conditions. An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 production. Several RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric- or allosteric-binding sites in the ligand-binding domain. Some of small-molecule inhibitors have entered clinical evaluations. Therefore, in current review, the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted. Notably, the recently developed RORγt inhibitors were summarized, with an emphasis on their optimization from lead compounds, efficacy, toxicity, mechanisms of action, and clinical trials. The limitations of current development in this area were also discussed to facilitate future research.
  • loading
  • S. Rutz, C. Eidenschenk, J.R. Kiefer, et al., Post-translational regulation of RORγt-A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases, Cytokine Growth Factor Rev. 30 (2016) 1-17.
    L.A. Solt, T.P. Burris, Action of RORs and their ligands in (patho)physiology, Trends Endocrinol. Metabol. 23 (2012) 619-627.
    M. Becker-Andre, E. Andre, J.F. DeLamarter, Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences, Biochem. Biophys. Res. Commun. 194 (1993) 1371-1379.
    C. Carlberg, R. Hooft van Huijsduijnen, J.K. Staple, et al., RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers, Mol. Endocrinol. 8 (1994) 757-770.
    T. Hirose, R.J. Smith, A.M. Jetten, RORγ: the third member of ROR/RZR α receptor subfamily that is highly expressed in skeletal muscle, Biochem. Biophys. Res. Commun. 205 (1994) 1976-1983.
    Ivanov, II, B.S. McKenzie, L. Zhou, et al., The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell. 126 (2006) 1121-1133.
    Y. Tian, Y. Wu, B. Ni, Signaling pathways and epigenetic regulations in the control of RORγt expression in T helper 17 cells, Int. Rev. Immunol. 34 (2015) 305-317.
    R. Kumar, A.L. Theiss, K. Venuprasad, RORγt protein modifications and IL-17-mediated inflammation, Trends Immunol. 42 (2021) 1037-1050.
    M.J. McGeachy, D.J. Cua, S.L. Gaffen, The IL-17 family of cytokines in health and disease, Immunity. 50 (2019) 892-906.
    J. Yang, M.S. Sundrud, J. Skepner, et al., Targeting Th17 cells in autoimmune diseases, Trends Pharmacol. Sci. 35 (2014) 493-500.
    M. Pelletier, L. Maggi, A. Micheletti, et al., Evidence for a cross-talk between human neutrophils and Th17 cells, Blood. 115 (2010) 335-343.
    G.K. Griffin, G. Newton, M.L. Tarrio, et al., IL-17 and TNF-α sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation, J. Immunol. 188 (2012) 6287-6299.
    L.A. Tesmer, S.K. Lundy, S. Sarkar, et al., Th17 cells in human disease, Immunol. Rev. 223 (2008) 87-113.
    I. Nomura, B. Gao, M. Boguniewicz, et al., Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis, J. Allergy Clin. Immunol. 112 (2003) 1195-1202.
    J.E. Hawkes, T.C. Chan, J.G. Krueger, Psoriasis pathogenesis and the development of novel targeted immune therapies, J. Allergy Clin. Immunol. 140 (2017) 645-653.
    E.G. Harper, C. Guo, H. Rizzo, et al., Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis, J. Invest. Dermatol. 129 (2009) 2175-2183.
    J.J. Campbell, K. Ebsworth, L.S. Ertl, et al., IL-17-secreting γδ T cells are completely dependent upon CCR6 for homing to inflamed skin, J. Immunol. 199 (2017) 3129-3136.
    E. Lubberts, L.A. Joosten, F.A. van de Loo, et al., Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction, Inflamm. Res. 51 (2002) 102-104.
    M.I. Koenders, E. Lubberts, B. Oppers-Walgreen, et al., Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1, Am. J. Pathol. 167 (2005) 141-149.
    K. Hirota, H. Yoshitomi, M. Hashimoto, et al., Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model, J. Exp. Med. 204 (2007) 2803-2812.
    2022 Alzheimer's disease facts and figures, Alzheimers Dement. 18 (2022) 700-789.
    Y. Hou, X. Dan, M. Babbar, et al., Ageing as a risk factor for neurodegenerative disease, Nat. Rev. Neurol. 15 (2019) 565-581.
    G.G. Glenner, C.W. Wong. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem. Biophys. Res. Commun. 120 (1984) 885-890.
    N. Nukina, Y. Ihara. One of the antigenic determinants of paired helical filaments is related to tau protein, J. Biochem. 99 (1986) 1541-1544.
    M.M. Corrada, D.J. Berlau, C.H. Kawas. A population-based clinicopathological study in the oldest-old: The 90+ study, Curr. Alzheimer Res. 9 (2012) 709-717.
    J.L. Robinson, M.M. Corrada, G.G. Kovacs, et al., Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study, Acta. Neuropathol. 136 (2018) 377-388.
    B.G. Perez-Nievas, T.D. Stein, H.C. Tai, et al., Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology, Brain. 136 (2013) 2510-2526.
    I. Barroeta-Espar, L.D. Weinstock, B.G. Perez-Nievas, et al., Distinct cytokine profiles in human brains resilient to Alzheimer's pathology, Neurobiol. Dis. 121 (2019) 327-337.
    F. Leng, P. Edison. Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here?, Nat. Rev. Neurol. 17 (2021) 157-172.
    R.M. Ransohoff. A polarizing question: Do M1 and M2 microglia exist?, Nat. Neurosci. 19 (2016) 987-991.
    S. Rangaraju, E.B. Dammer, S.A. Raza, et al., Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease, Mol. Neurodegener. 13 (2018), 24.
    M. Plescher, G. Seifert, J.N. Hansen, et al., Plaque-dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model, Glia. 66 (2018) 1464-1480.
    H. Li, M. Wei, T. Ye, et al., Identification of the molecular subgroups in Alzheimer's disease by transcriptomic data, Front. Neurol. 13 (2022), 901179.
    R. Satija, J.A. Farrell, D. Gennert, et al., Spatial reconstruction of single-cell gene expression data, Nat. Biotechnol. 33 (2015) 495-502.
    Q. Zhang, Y. He, N. Luo, et al., Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma, Cell. 179 (2019) 829-845.e20.
    J.H. Levine, E.F. Simonds, S.C. Bendall, et al., Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis, Cell. 162 (2015) 184-197.
    D. Kobak, P. Berens. The art of using t-SNE for single-cell transcriptomics, Nat. Commun. 10 (2019), 5416.
    V. Ntranos, L. Yi, P. Melsted, et al., A discriminative learning approach to differential expression analysis for single-cell RNA-seq, Nat. Methods. 16 (2019) 163-166.
    S. Jin, C.F. Guerrero-Juarez, L. Zhang, et al., Inference and analysis of cell-cell communication using CellChat, Nat. Commun. 12 (2021), 1088.
    H. Oakley, S.L. Cole, S. Logan, et al., Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation, J. Neurosci. 26 (2006) 10129-10140.
    A. Giladi, M. Cohen, C. Medaglia, et al., Dissecting cellular crosstalk by sequencing physically interacting cells, Nat. Biotechnol. 38 (2020) 629-637.
    R. Vento-Tormo, M. Efremova, R.A. Botting, et al., Single-cell reconstruction of the early maternal-fetal interface in humans, Nature. 563 (2018) 347-353.
    M.D. Sweeney, Z. Zhao, A. Montagne, et al., Blood-Brain Barrier: From Physiology to Disease and Back, Physiol. Rev. 99 (2019) 21-78.
    M.D. Sweeney, A.P. Sagare, B.V. Zlokovic. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders, Nat. Rev. Neurol. 14 (2018) 133-150.
    D. Gomez-Nicola, N.L. Fransen, S. Suzzi, et al., Regulation of microglial proliferation during chronic neurodegeneration, J. Neurosci. 33 (2013) 2481-2493.
    J. Yao, M. Zhang, Q.Y. Ma, et al., PAd-shRNA-PTN reduces pleiotrophin of pancreatic cancer cells and inhibits neurite outgrowth of DRG, World J. Gastroenterol. 17 (2011) 2667-2673.
    I.S. Lee, K. Jung, I.S. Kim, et al., Human neural stem cells alleviate Alzheimer-like pathology in a mouse model, Mol. Neurodegener. 10 (2015), 38.
    S.B. Rangasamy, M. Jana, A. Roy, et al., Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology, J. Clin. Invest. 128 (2018) 4297-4312.
    S.J. Tsai. Effects of interleukin-1beta polymorphisms on brain function and behavior in healthy and psychiatric disease conditions, Cytokine Growth Factor. Rev. 37 (2017) 89-97.
    V. Pons, P. Levesque, M.M. Plante, et al., Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer's disease, Alzheimers Res. Ther. 13 (2021), 8.
    N. Piehl, L. van Olst, A. Ramakrishnan, et al., Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment, Cell. 185 (2022) 5028-5039.e13.
    S.M. Pyonteck, L. Akkari, A.J. Schuhmacher, et al., CSF-1R inhibition alters macrophage polarization and blocks glioma progression, Nat. Med. 19 (2013) 1264-1272.
    L.J. Lawson, V.H. Perry, P. Dri, et al., Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain, Neuroscience. 39 (1990) 151-170.
    J. Bruttger, K. Karram, S. Wortge, et al., Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System, Immunity. 43 (2015) 92-106.
    R.C. Paolicelli, G. Bolasco, F. Pagani, et al., Synaptic pruning by microglia is necessary for normal brain development, Science. 333 (2011) 1456-1458.
    C.N. Parkhurst, G. Yang, I. Ninan, et al., Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor, Cell. 155 (2013) 1596-1609.
    M. Colonna, O. Butovsky. Microglia Function in the Central Nervous System During Health and Neurodegeneration, Annu. Rev. Immunol. 35 (2017) 441-468.
    A. Serrano-Pozo, M.L. Mielke, T. Gomez-Isla, et al., Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease, Am. J. Pathol. 179 (2011) 1373-1384.
    H. Zhang, W. Wei, M. Zhao, et al., Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease, Int. J. Biol. Sci. 17 (2021) 2181-2192.
    S.R. Guttikonda, L. Sikkema, J. Tchieu, et al., Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease, Nat. Neurosci. 24 (2021) 343-354.
    R.M. Ransohoff. How neuroinflammation contributes to neurodegeneration, Science. 353 (2016) 777-783.
    X. Chen, M. Firulyova, M. Manis, et al., Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy, Nature. 615 (2023) 668-677.
    S.C. Hopp, Y. Lin, D. Oakley, et al., The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer's disease, J. Neuroinflammation. 15 (2018), 269.
    K. Bhaskar, M. Konerth, O.N. Kokiko-Cochran, et al., Regulation of tau pathology by the microglial fractalkine receptor, Neuron. 68 (2010) 19-31.
    R.N. Taddei, M.V. Sanchez-Mico, O. Bonnar, et al., Changes in glial cell phenotypes precede overt neurofibrillary tangle formation, correlate with markers of cortical cell damage, and predict cognitive status of individuals at Braak III-IV stages, Acta. Neuropathol. Commun. 10 (2022), 72.
    D. Krstic, A. Madhusudan, J. Doehner, et al., Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice, J. Neuroinflammation. 9 (2012), 151.
    D.S. Davies, J. Ma, T. Jegathees, et al., Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease, Brain Pathol. 27 (2017) 795-808.
    D.J. DiSabato, N. Quan, J.P. Godbout. Neuroinflammation: The devil is in the details, J. Neurochem. 139 Suppl 2 (2016) 136-153.
    H.L. McConnell, C.N. Kersch, R.L. Woltjer, et al., The Translational Significance of the Neurovascular Unit, J. Biol. Chem. 292 (2017) 762-770.
    Y.M. Qiu, C.L. Zhang, A.Q. Chen, et al., Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?, Front. Immunol. 12 (2021), 678744.
    V. Jolivel, F. Bicker, F. Biname, et al., Perivascular microglia promote blood vessel disintegration in the ischemic penumbra, Acta. Neuropathol. 129 (2015) 279-295.
    C. Wallet, M. De Rovere, J. Van Assche, et al., Microglial Cells: The Main HIV-1 Reservoir in the Brain, Front. Cell. Infect. Microbiol. 9 (2019), 362.
    P. Chauhan, S. Hu, W.S. Sheng, et al., Regulatory T-Cells Suppress Cytotoxic T Lymphocyte Responses against Microglia, Cells. 11 (2022), 2826.
    E.N. Goddery, C.E. Fain, C.G. Lipovsky, et al., Microglia and Perivascular Macrophages Act as Antigen Presenting Cells to Promote CD8 T Cell Infiltration of the Brain, Front Immunol. 12 (2021), 726421.
    M.S. Tsai, L.C. Wang, H.Y. Tsai, et al., Microglia Reduce Herpes Simplex Virus 1 Lethality of Mice with Decreased T Cell and Interferon Responses in Brains, Int. J. Mol. Sci. 22 (2021), 12457.
    B.W. Dulken, M.T. Buckley, P. Navarro Negredo, et al., Single-cell analysis reveals T cell infiltration in old neurogenic niches, Nature. 571 (2019) 205-210.
    J. Yan, W. Xu, C. Lenahan, et al., CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage, Stroke. 52 (2021) 4021-4032.
    P. Chauhan, W.S. Sheng, S. Hu, et al., Differential Cytokine-Induced Responses of Polarized Microglia, Brain Sci. 11 (2021),1482.
    D. Hefter, S. Ludewig, A. Draguhn, et al., Amyloid, APP, and Electrical Activity of the Brain, Neuroscientist. 26 (2020) 231-251.
    D. Matza, A. Kerem, I. Shachar. Invariant chain, a chain of command, Trends Immunol. 24 (2003) 264-268.
    S. Matsuda, Y. Matsuda, L. D'Adamio. CD74 interacts with APP and suppresses the production of Abeta, Mol. Neurodegener. 4 (2009), 41.
    T. Kiyota, G. Zhang, C.M. Morrison, et al., AAV2/1 CD74 Gene Transfer Reduces β-amyloidosis and Improves Learning and Memory in a Mouse Model of Alzheimer's Disease, Mol. Ther. 23 (2015) 1712-1721.
    B. Erblich, L. Zhu, A.M. Etgen, et al., Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits, PLoS One. 6 (2011), e26317.
    Y.J. Liu, E.E. Spangenberg, B. Tang, et al., Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex, J. Neurosci. 41 (2021) 1274-1287.
    X. Feng, M. Valdearcos, Y. Uchida, et al., Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice, JCI. Insight. 2 (2017), e91229.
    S. Wu, R. Xue, S. Hassan, et al., Il34-Csf1r Pathway Regulates the Migration and Colonization of Microglial Precursors, Dev. Cell. 46 (2018) 552-563.e4.
    H.S. Suh, M.L. Zhao, L. Derico, et al., Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: Differential regulation by inflammatory mediators, J. Neuroinflammation. 10 (2013), 37.
    M.J. Carson, R.R. Behringer, R.L. Brinster, et al., Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice, Neuron. 10 (1993) 729-740.
    Z. Cao, S.S. Harvey, T. Chiang, et al., Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke, Stroke. 52 (2021) 687-698.
    X. Shen, Y. Qiu, A.E. Wight, et al., Definition of a mouse microglial subset that regulates neuronal development and proinflammatory responses in the brain, Proc. Natl. Acad .Sci. U S A. 119 (2022), e2116241119.
    S. Krasemann, C. Madore, R. Cialic, et al., The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases, Immunity. 47 (2017) 566-581.e569.
    L. Hou, R.A. Voit, V.G. Sankaran, et al., CD11c regulates hematopoietic stem and progenitor cells under stress, Blood Adv. 4 (2020) 6086-6097.
    J. Helft, J. Bottcher, P. Chakravarty, et al., GM-CSF Mouse Bone Marrow Cultures Comprise a Heterogeneous Population of CD11c(+)MHCII(+) Macrophages and Dendritic Cells, Immunity. 42 (2015) 1197-1211.
    S.R. Anderson, J.M. Roberts, J. Zhang, et al., Developmental Apoptosis Promotes a Disease-Related Gene Signature and Independence from CSF1R Signaling in Retinal Microglia, Cell Rep. 27 (2019) 2002-2013.e2005.
    K. Kohno, R. Shirasaka, K. Yoshihara, et al., A spinal microglia population involved in remitting and relapsing neuropathic pain, Science. 376 (2022) 86-90.
    Y. Shi, D.M. Holtzman. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight, Nat. Rev. Immunol. 18 (2018) 759-772.
    S. Rangaraju, S.A. Raza, N.X. Li, et al., Differential Phagocytic Properties of CD45(low) Microglia and CD45(high) Brain Mononuclear Phagocytes-Activation and Age-Related Effects, Front. Immunol. 9 (2018), 405.
    S. Goudarzi, S.E. Gilchrist, S. Hafizi. Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia, Cells. 9 (2020), 1779.
    Y. Huang, K.E. Happonen, P.G. Burrola, et al., Microglia use TAM receptors to detect and engulf amyloid β plaques, Nat. Immunol. 22 (2021) 586-594.
    L. Fourgeaud, P.G. Traves, Y. Tufail, et al., TAM receptors regulate multiple features of microglial physiology, Nature. 532 (2016) 240-244.
    J.Y. Kim, J. Kim, M. Huang, et al., CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation, Front. Immunol. 13 (2022), 876033.
    K. Haruwaka, A. Ikegami, Y. Tachibana, et al., Dual microglia effects on blood brain barrier permeability induced by systemic inflammation, Nat. Commun. 10 (2019), 5816.
    M.T. Joy, E. Ben Assayag, D. Shabashov-Stone, et al., CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury, Cell. 176 (2019) 1143-1157.e13.
    C. Maudet, M. Kheloufi, S. Levallois, et al., Bacterial inhibition of Fas-mediated killing promotes neuroinvasion and persistence, Nature. 603 (2022) 900-906.
    M. Mizutani, P.A. Pino, N. Saederup, et al., The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood, J. Immunol. 188 (2012) 29-36.
    B.D. Semple, N. Bye, M. Rancan, et al., Role of CCL2 (MCP-1) in traumatic brain injury (TBI): Evidence from severe TBI patients and CCL2-/- mice, J. Cereb Blood Flow Metab. 30 (2010) 769-782.
    C.L. Hsieh, E.C. Niemi, S.H. Wang, et al., CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury, J. Neurotrauma. 31 (2014) 1677-1688.
    K. Somebang, J. Rudolph, I. Imhof, et al., CCR2 deficiency alters activation of microglia subsets in traumatic brain injury, Cell Rep. 36 (2021), 109727.
    B. Spittau, N. Dokalis, M. Prinz. The Role of TGFβ Signaling in Microglia Maturation and Activation, Trends Immunol. 41 (2020) 836-848.
    K. Yoshinaga, H. Obata, V. Jurukovski, et al., Perturbation of transforming growth factor (TGF)-beta1 association with latent TGF-beta binding protein yields inflammation and tumors, Proc. Natl Acad. Sci. U S A. 105 (2008) 18758-18763.
    T.C. Brionne, I. Tesseur, E. Masliah, et al., Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain, Neuron. 40 (2003) 1133-1145.
    S.E. Hickman, N.D. Kingery, T.K. Ohsumi, et al., The microglial sensome revealed by direct RNA sequencing, Nat. Neurosci. 16 (2013) 1896-1905.
    A. Buttgereit, I. Lelios, X. Yu, et al., Sall1 is a transcriptional regulator defining microglia identity and function, Nat. Immunol. 17 (2016) 1397-1406.
    T. Zoller, A. Schneider, C. Kleimeyer, et al., Silencing of TGFβ signalling in microglia results in impaired homeostasis, Nat. Commun. 9 (2018), 4011.
    S. Danese, L. Peyrin-Biroulet, Selective tyrosine kinase 2 inhibition for treatment of inflammatory bowel disease: new hope on the rise, Inflamm. Bowel Dis. 27 (2021) 2023-2030.
    D. Wu, X.O. Yang, Th17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib, J. Microbiol. Immunol. Infect. 53 (2020) 368-370.
    G.M. Keating, Apremilast: a review in psoriasis and psoriatic arthritis, Drugs. 77 (2017) 459-472.
    L. Tang, X. Yang, Y. Liang, et al., Transcription factor retinoid-related orphan receptor γt: a promising target for the treatment of psoriasis, Front. Immunol. 9 (2018), 1210.
    K.E. Nograles, L.C. Zaba, E. Guttman-Yassky, et al., Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways, Br. J. Dermatol. 159 (2008) 1092-1102.
    K. Guilloteau, I. Paris, N. Pedretti, et al., Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of psoriasis, J. Immunol. 184 (2010) 5263-5270.
    C. Gege, Retinoic acid-related orphan receptor γt (RORγt) inverse agonists/antagonists for the treatment of inflammatory diseases - where are we presently?, Expet Opin. Drug Discov. 16 (2021) 1517-1535.
    Y. Sasaki, M. Odan, S. Yamamoto, et al., Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-γt (RORγt) inhibitor, S18-000003, Bioorg. Med. Chem. Lett. 28 (2018) 3549-3553.
    C. Imura, A. Ueyama, Y. Sasaki, et al., A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations, J. Dermatol. Sci. 93 (2019) 176-185.
    M. Takaishi, M. Ishizaki, K. Suzuki, et al., Oral administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17, J. Dermatol. Sci. 85 (2017) 12-19.
    S. Liu, D. Liu, R. Shen, et al., Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis, Sci. Rep. 11 (2021), 9132.
    S. Hintermann, C. Guntermann, H. Mattes, et al., Synthesis and biological evaluation of new triazolo- and imidazolopyridine RORγt inverse agonists, ChemMedChem. 11 (2016) 2640-2648.
    F. Ecoeur, J. Weiss, K. Kaupmann, et al., Antagonizing retinoic acid-related-orphan receptor γ activity blocks the T helper 17/interleukin-17 pathway leading to attenuated pro-inflammatory human keratinocyte and skin responses, Front. Immunol. 10 (2019), 577.
    J. Skepner, M. Trocha, R. Ramesh, et al., In vivo regulation of gene expression and T helper type 17 differentiation by RORγt inverse agonists, Immunology. 145 (2015) 347-356.
    J. Skepner, R. Ramesh, M. Trocha, et al., Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo, J. Immunol. 192 (2014) 2564-2575.
    R.J. Cherney, L.A.M. Cornelius, A. Srivastava, et al., Discovery of BMS-986251: a clinically viable, potent, and selective RORγt inverse agonist, ACS Med. Chem. Lett. 11 (2020) 1221-1227.
    H.G. Haggerty, J.G. Sathish, C.R. Gleason, et al., Thymic lymphomas in a 6-Month rasH2-Tg mouse carcinogenicity study with the RORγt inverse agonist, BMS-986251, Toxicol. Sci. 183 (2021) 93-104.
    M.G. Yang, M. Beaudoin-Bertrand, Z. Xiao, et al., Tricyclic-carbocyclic RORγt inverse agonists-discovery of BMS-986313, J. Med. Chem. 64 (2021) 2714-2724.
    S.B. Gauld, S. Jacquet, D. Gauvin, et al., Inhibition of interleukin-23-mediated inflammation with a novel small molecule inverse agonist of RORγt, J. Pharmacol. Exp. Therapeut. 371 (2019) 208-218.
    J.R. Huh, M.W. Leung, P. Huang, et al., Digoxin and its derivatives suppress Th17 cell differentiation by antagonizing RORγt activity, Nature. 472 (2011) 486-490.
    S. Fujita-Sato, S. Ito, T. Isobe, et al., Structural basis of digoxin that antagonizes RORγt receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production, J. Biol. Chem. 286 (2011) 31409-31417.
    J. Lee, S. Baek, J. Lee, et al., Digoxin ameliorates autoimmune arthritis via suppression of Th17 differentiation, Int. Immunopharm. 26 (2015) 103-111.
    J. Ji, H. Dou, X. Li, et al., Novel benzenediamine derivative FC99 ameliorates zymosan-induced arthritis by inhibiting RORγt expression and Th17 cell differentiation, Acta Biochim. Biophys. Sin. 46 (2014) 829-836.
    U. Guendisch, J. Weiss, F. Ecoeur, et al., Pharmacological inhibition of RORγt suppresses the Th17 pathway and alleviates arthritis in vivo, PLoS One. 12 (2017), e0188391.
    X. Xue, A. De Leon-Tabaldo, R. Luna-Roman, et al., Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534, Sci. Rep. 11 (2021), 11066.
    X. Xue, P. Soroosh, A. De Leon-Tabaldo, et al., Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis, Sci. Rep. 6 (2016), 37977.
    M.R. Chang, B. Lyda, T.M. Kamenecka, et al., Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor γ is therapeutic in the collagen-induced arthritis experimental model, Arthritis Rheumatol. 66 (2014) 579-588.
    T. Aranami, T. Yamamura, Th17 cells and autoimmune encephalomyelitis (EAE/MS), Allergol. Int. 57 (2008) 115-120.
    M. El-Behi, B. Ciric, H. Dai, et al., The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF, Nat. Immunol. 12 (2011) 568-575.
    Z. Etesam, M. Nemati, M.A. Ebrahimizadeh, et al., Altered expression of specific transcription factors of Th17 (RORγt, RORα) and Treg lymphocytes (FOXP3) by peripheral blood mononuclear cells from patients with multiple sclerosis, J. Mol. Neurosci. 60 (2016) 94-101.
    T. Xu, X. Wang, B. Zhong, et al., Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORγt protein, J. Biol. Chem. 286 (2011) 22707-22710.
    L.A. Solt, N. Kumar, P. Nuhant, et al., Suppression of Th17 differentiation and autoimmunity by a synthetic ROR ligand, Nature. 472 (2011) 491-494.
    Y. Fukase, A. Sato, Y. Tomata, et al., Identification of novel quinazolinedione derivatives as RORγt inverse agonist, Bioorg. Med. Chem. 26 (2018) 721-736.
    C. Gege, T. Schluter, T. Hoffmann, Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt, Bioorg. Med. Chem. Lett. 24 (2014) 5265-5267.
    Y. Wang, W. Cai, G. Zhang, et al., Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors, Bioorg. Med. Chem. 22 (2014) 692-702.
    M. Kono, A. Ochida, T. Oda, et al., Discovery of [ cis-3-({(5R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic acid (TAK-828F) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist, J. Med. Chem. 61 (2018) 2973-2988.
    H. Nakagawa, R. Koyama, Y. Kamada, et al., Biochemical properties of TAK-828F, a potent and selective retinoid-related orphan receptor γt inverse agonist, Pharmacology. 102 (2018) 244-252.
    Y. Nakamura, K. Igaki, K. Uga, et al., Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine chronic experimental autoimmune encephalomyelitis model, J. Neuroimmunol. 335 (2019), 577016.
    S. Xiao, N. Yosef, J. Yang, et al., Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms, Immunity. 40 (2014) 477-489.
    N. Kumar, B. Lyda, M.R. Chang, et al., Identification of SR2211: a potent synthetic RORγ-selective modulator, ACS Chem. Biol. 7 (2012) 672-677.
    F. Caprioli, F. Pallone, G. Monteleone, Th17 immune response in IBD: a new pathogenic mechanism, J. Crohns Colitis. 2 (2008) 291-295.
    S. Fujino, A. Andoh, S. Bamba, et al., Increased expression of interleukin 17 in inflammatory bowel disease, Gut. 52 (2003) 65-70.
    T. Kobayashi, S. Okamoto, T. Hisamatsu, et al., IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and crohn's disease, Gut. 57 (2008) 1682-1689.
    M. Leppkes, C. Becker, Ivanov, II, et al., RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F, Gastroenterology. 136 (2009) 257-267.
    K. Igaki, Y. Nakamura, M. Tanaka, et al., Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease, Inflamm. Res. 68 (2019) 493-509.
    A. Shibata, K. Uga, T. Sato, et al., Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist, Biochem. Pharmacol. 150 (2018) 35-45.
    K. Igaki, Y. Nakamura, Y. Komoike, et al., Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine colitis model, Inflammation. 42 (2019) 91-102.
    D.R. Withers, M.R. Hepworth, X. Wang, et al., Transient inhibition of RORγt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells, Nat. Med. 22 (2016) 319-323.
    L.R. Fitzpatrick, J. Small, R. O'Connell, et al., VPR-254: an inhibitor of RORγt with potential utility for the treatment of inflammatory bowel disease, Inflammopharmacology. 28 (2020) 499-511.
    H. Bassolas-Molina, E. Raymond, M. Labadia, et al., An RORγt oral inhibitor modulates IL-17 responses in peripheral blood and intestinal mucosa of crohn's disease patients, Front. Immunol. 9 (2018), 2307.
    J.A. Chen, H. Ma, Z. Liu, et al., Discovery of orally available retinoic acid receptor-related orphan receptor γt/dihydroorotate dehydrogenase dual inhibitors for the treatment of refractory inflammatory bowel disease, J. Med. Chem. 65 (2022) 592-615.
    C. Lyu, S.J. Bing, W.S. Wandu, et al., TMP778, a selective inhibitor of RORγt, suppresses experimental autoimmune uveitis development, but affects both Th17 and Th1 cell populations, Eur. J. Immunol. 48 (2018) 1810-1816.
    J. Tan, H. Liu, M. Huang, et al., Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation, Cell Death Dis. 11 (2020), 697.
    S. Ano, Y. Morishima, Y. Ishii, et al., Transcription factors GATA-3 and RORγt are important for determining the phenotype of allergic airway inflammation in a murine model of asthma, J. Immunol. 190 (2013) 1056-1065.
    D. Lamb, D. De Sousa, K. Quast, et al., RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma, Respir. Res. 22 (2021), 158.
    G.S. Whitehead, H.S. Kang, S.Y. Thomas, et al., Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by a RORγt inverse agonist, JCI Insight. 5 (2019), 125528.
    C. Harcken, J. Csengery, M. Turner, et al., Discovery of a series of pyrazinone RORγ antagonists and identification of the clinical candidate BI 730357, ACS Med. Chem. Lett. 12 (2021) 143-154.
    U.S. National Library of Medicine. Study to evaluate the efficacy and safety of JTE-451 in subjects with moderate to severe plaque psoriasis (IMPACT-PS). https://clinicaltrials.gov/ct2/show/NCT03832738?cond=NCT03832738&draw=2&rank=1. (Accessed 6 April 2023).
    U.S. National Library of Medicine. A study in healthy men to test how BI 730357 is processed by the body. https://clinicaltrials.gov/ct2/show/NCT03664011?cond=BI+730357&draw=2&rank=1. (Accessed 12 April 2023).
    U.S. National Library of Medicine. This study is done in patients with plaque psoriasis and tests how well they tolerate BI 730357 and how effective it is. https://clinicaltrials.gov/ct2/show/NCT03635099?cond=BI+730357&draw=2&rank=3. (Accessed 12 April 2023).
    U.S. National Library of Medicine. A study to evaluate the pharmacokinetics, safety and tolerability of ABBV-157 in healthy volunteers and in participants with chronic plaque psoriasis. https://clinicaltrials.gov/ct2/show/NCT03922607?cond=ABBV-157&draw=2&rank=2. (Accessed 12 April 2023).
    U.S. National Library of Medicine. A study to assess adverse events and disease activity with cedirogant (ABBV-157) in adult participants with moderate to severe psoriasis. https://clinicaltrials.gov/ct2/show/NCT05044234?cond=ABBV-157&draw=2&rank=1> (Accessed 11 April 2023).
    U.S. National Library of Medicine. Safety and PK/PD of RTA 1701 in healthy adults. https://clinicaltrials.gov/ct2/show/NCT03579030?cond=RTA-1701&draw=2&rank=1. (Accessed 25 March 2023).
    U.S. National Library of Medicine. A phase II study to evaluate efficacy & safety of AUR101 in patients of moderate-to-severe psoriasis (INDUS-2). https://clinicaltrials.gov/ct2/show/NCT04207801?cond=AUR-101&draw=2&rank=1s. (Accessed 25 March 2023).
    E.G. Kang, S. Wu, A. Gupta, et al., A phase I randomized controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test, Br. J. Dermatol. 178 (2018) 1427-1429.
    G. Berstein, Y. Zhang, Z. Berger, et al., A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis, Clin. Exp. Dermatol. 46 (2021) 122-129.
    M.E. Schnute, J.I. Trujillo, K.L. Lee, et al., Macrocyclic retinoic acid receptor-related orphan receptor C2 inverse agonists, ACS Med. Chem. Lett. 14 (2023) 191-198.
    C. Gege, Retinoid-related orphan receptor γt (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742, Expert Opin. Ther. Pat. 26 (2016) 737-744.
    C. Gege, RORγt inhibitors as potential back-ups for the phase II candidate VTP-43742 from Vitae Pharmaceuticals: patent evaluation of WO2016061160 and US20160122345, Expert Opin. Ther. Pat. 27 (2017) 1-8.
    S. Asimus, R. Palmer, M. Albayaty, et al., Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284, Br. J. Clin. Pharmacol. 86 (2020) 1398-1405.
    F. Narjes, A. Llinas, S. von Berg, et al., AZD0284, a potent, selective, and orally bioavailable inverse agonist of retinoic acid receptor-related orphan receptor C2, J. Med. Chem. 64 (2021) 13807-13829.
    U.S. National Library of Medicine. Study to determine if AZD0284 is effective and safe in treating plaque psoriasis (DERMIS). https://clinicaltrials.gov/ct2/show/NCT03310320?cond=AZD0284&draw=2&rank=2. (Accessed 28 March 2023).
    Y. Guo, K.D. MacIsaac, Y. Chen, et al., Inhibition of RORγt skews TCRα gene rearrangement and limits T cell repertoire diversity, Cell Rep. 17 (2016) 3206-3218.
    C. Guntermann, A. Piaia, M.L. Hamel, et al., Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations, JCI Insight. 2 (2017), e91127.
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)

    Article Metrics

    Article views (332) PDF downloads(34) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return