IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?

Biswas, Partha S.; Bhagat, Govind; Pernis, Alessandra B.

doi:10.1111/j.0105-2896.2009.00864.x

Cited by 75 publications

(82 citation statements)

References 178 publications

(328 reference statements)

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“…IRF4 is known to interact with a number of other transcription factors, including ETS factors and AP1 family members. In different settings, these interactions are critical in determining the DNA-binding specificity and functional nature of the IAD, either as an activator or repressor of transcription [91][92][93]. However, whether these interactions occur within the context of DCs remain to be defined, although PU.1 (ETS) and Batf3 (AP1) are attractive candidates.…”

Section: Factors Regulating Late DC Progenitor Developmentmentioning

confidence: 99%

Transcription factor networks in dendritic cell development

Satpathy

Murphy

2011

Seminars in Immunology

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Dendritic cells (DCs) are a heterogeneous population within the mononuclear phagocyte system (MPS) that derive from bone marrow precursors. Commitment and specification of hematopoietic progenitors to the DC lineage is critical for the proper induction of both immunity and tolerance. This review summarizes the important cytokines and transcription factors required for differentiation of the DC lineage as well as further diversification into specific DC subsets. We highlight recent advances in the characterization of immediate DC precursors arising from the common myeloid progenitor (CMP). Particular emphasis is placed on the corresponding temporal expression of relevant factors involved in regulating developmental options.

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Section: Factors Regulating Late DC Progenitor Developmentmentioning

confidence: 99%

Transcription factor networks in dendritic cell development

Satpathy

Murphy

2011

Seminars in Immunology

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“…The Rho kinase family members, consisting of Rho-associated kinase 1 (ROCK1) and ROCK2, are serine-threonine kinases that are activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells (9). Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10,11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12).…”

mentioning

confidence: 99%

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Zanin-Zhorov¹,

Weiss²,

Nyuydzefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

201

214

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Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.T he immune response is a delicate balancing act, protecting the integrity of the host organism from foreign invaders while not causing autoimmune reactivity (1). IL-21 and IL-17 are proinflammatory cytokines produced by T-helper 17 (Th17) cells that are involved in the pathogenesis of many autoimmune diseases (2-5). The generation of Th17 cells is induced by a combination of several cytokines including transforming growth factor-β (TGF-β1), IL-1β, IL-6, and IL-23, and involves the activation of transcription factors, such as RAR-related orphan receptor (ROR) γt, RORα, IFN regulatory factor (IRF) 4, and signal transducer and activator of transcription 3 (STAT3) (2, 6, 7). However, the signaling pathways that lead to activation of this transcriptional profile are poorly understood and remain unclear.Rho GTPase-mediated signaling pathways play a central role in the coordination and balancing of T-cell-mediated immune responses, including T-cell receptor (TCR)-mediated signaling, cytoskeletal reorganization, and the acquisition of the appropriate T-cell effector program (8). The Rho kinase family members, consisting of Rho-associated kinase 1 (ROCK1) and ROCK2, are serine-threonine kinases that are activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells (9). Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10, 11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12). Additionally, ROCK activity was found to be up-regulated in patients w...

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“…Consistent with these data, our adoptive transfer study showed that IRF4 deficiency in effector T cells conferred disease resistance in recipient mice in a gene-dose-dependent manner. These results suggest that the dosage of IRF4 affects the function of autoreactive Cell number, ×10 6 …”

Section: Discussionmentioning

confidence: 90%

“…A series of reports have documented that IRF4 plays pleiotropic roles in lymphoid development and its immune response [6,7]. At the molecular level, studies have suggested that IRF4, together with BATF (basic leucine zipper transcription factor ATF-like) and the activator protein-1 family member JUN, acts as a 'pioneer transcriptional factor' that prepares chromatin accessibility for the subsequent lineage-specific transcriptional factor and drives gene expression for the differentiation of effector T cells [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…At the molecular level, studies have suggested that IRF4, together with BATF (basic leucine zipper transcription factor ATF-like) and the activator protein-1 family member JUN, acts as a 'pioneer transcriptional factor' that prepares chromatin accessibility for the subsequent lineage-specific transcriptional factor and drives gene expression for the differentiation of effector T cells [8][9][10]. It has been documented that IRF4 is necessary for the differentiation of diverse effector CD4 + T cell subsets, including helper T cell (Th) types 2 [11][12][13], Th9 [14] and Th17 [6,15,16], follicular Th cells [17], the sustained effector function of cytotoxic T cells [18][19][20], the regulation of effector regulatory T cells (Tregs) [21], the series of developmental stages of B cells [17,[22][23][24][25][26] and the development and function of dendritic cells (DCs) [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

et al. 2015

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Aims/hypothesis: Interferon regulatory factor (IRF)4 plays a critical role in lymphoid development and the regulation of immune responses. Genetic deletion of IRF4 has been shown to suppress autoimmune disease in several mouse models, but its role in autoimmune diabetes in NOD mice remains unknown. Methods:To address the role of IRF4 in the pathogenesis of autoimmune diabetes in NOD mice, we generated IRF4-knockout NOD mice and investigated the impact of the genetic deletion of IRF4 on diabetes, insulitis and insulin autoantibody; the effector function of T cells in vivo and in vitro; and the proportion of dendritic cell subsets.Results: Heterozygous IRF4-deficient NOD mice maintained the number and phenotype of T cells at levels similar to NOD mice. However, diabetes and autoantibody production were completely suppressed in both heterozygous and homozygous IRF4-deficient NOD mice. The level of insulitis was strongly suppressed in both heterozygous and homozygous IRF4-deficient mice, with minimal insulitis observed in heterozygous mice. An adoptive transfer study revealed that IRF4 deficiency conferred disease resistance in a gene-dose-dependent manner in recipient NOD/severe combined immunodeficiency mice.Furthermore, the proportion of migratory dendritic cells in lymph nodes was reduced in 4 heterozygous and homozygous IRF4-deficient NOD mice in an IRF4 dose-dependent manner.These results suggest that the levels of IRF4 in T cells and dendritic cells are important for the pathogenesis of diabetes in NOD mice. Conclusions/interpretation:Haploinsufficiency of IRF4 halted disease development in NOD mice. Our findings suggest that an IRF4-targeted strategy might be useful for modulating autoimmunity in type 1 diabetes.

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IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?

Cited by 75 publications

References 178 publications

Transcription factor networks in dendritic cell development

Transcription factor networks in dendritic cell development

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

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