Therapeutic Effects of a <scp>TANK</scp>‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

Louis, Cynthia; Ngo, Devi; D'Silva, Damian B; Hansen, Jacinta; Phillipson, Louisa; Jousset, Hélène; Novello, Patrizia M; Segal, David; Lawlor, Kate E.; Burns, Christopher J.; Wicks, Ian P.

doi:10.1002/art.40670

Cited by 17 publications

(17 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistently, TBK1 was also dispensable for the development of nascent T FH cells, indicating that signals mediated by TBK1 binding to the ICOS IProx motif 'license' nascent T FH cells to enter the GC phase of T FH cell development. In agreement with our findings, it has recently been demonstrated that therapeutic inhibition of TBK1 reduced the number of GC T FH and their expression of Bcl6 , caused a reduction in GC size, diminished the anti-collagen Ab levels and alleviated the progression of established collagen induced arthritis ( 90 ).…”

Section: Molecular Interactions In T Fh Differentisupporting

confidence: 93%

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Pedros

Kong

2018

Front. Immunol.

View full text Add to dashboard Cite

Follicular helper T (TFH) cells represent a highly specialized CD4+ T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. TFH cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a TFH phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors. Members of the Tumor necrosis factor Receptor Associated Factors (TRAF) represent one of the major classes of signaling mediators involved in the differentiation and functions of TFH cells. TRAF molecules are the canonical adaptor molecules that physically interact with members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and actively modulate their downstream signaling cascades through their adaptor function and/or E3 ubiquitin ligase activity. OX-40, GITR, and 4-1BB are the TRAF-dependent TNFRSF members that have been implicated in the differentiation and functions of TFH cells. On the other hand, emerging data demonstrate that TRAF proteins also participate in signaling from the TCR and CD28, which deliver critical signals leading to the differentiation of TFH cells. More intriguingly, we recently showed that the cytoplasmic tail of ICOS contains a conserved TANK-binding kinase 1 (TBK1)-binding motif that is shared with TBK1-binding TRAF proteins. The presence of this TRAF-mimicking signaling module downstream of ICOS is required to mediate the maturation step during TFH differentiation. In addition, JAK-STAT pathways emanating from IL-2, IL-6, IL-21, and IL-27 cytokine receptors affect TFH development, and crosstalk between TRAF-mediated pathways and the JAK-STAT pathways can contribute to generate integrated signals required to drive and sustain TFH differentiation. In this review, we will introduce the molecular interactions and the major signaling pathways controlling the differentiation of TFH cells. In each case, we will highlight the contributions of TRAF proteins to these signaling pathways. Finally, we will discuss the role of individual TRAF proteins in the regulation of T cell-dependent humoral responses.

show abstract

Section: Molecular Interactions In T Fh Differentisupporting

confidence: 93%

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Pedros

Kong

2018

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Having established that TBK1 and IKKε act redundantly to drive STING-NF-kB, we next assessed the effects of inhibiting their kinase activity on STING responses. To do this, we pre-treated primary BMDMs with the semi-selective TBK1/IKKε kinase inhibitors, WEHI-112 (Louis et al, 2019) or MRT67307, using DMSO as a vehicle Ctrl, 1 h prior to STING activation. As previously reported, we observed paradoxical autophosphorylation of TBK1 in the presence of WEHI-112 and MRT67307 (Louis et al, 2019), but a loss of DMXAA-induced p-IRF3 (Figure S3A).…”

Section: Sting-induced Nf-kb Responses Are Less Sensitive To Tbk1 and Ikkε Kinase Inhibition Than Type I Ifnsmentioning

confidence: 99%

“…To do this, we pre-treated primary BMDMs with the semi-selective TBK1/IKKε kinase inhibitors, WEHI-112 (Louis et al, 2019) or MRT67307, using DMSO as a vehicle Ctrl, 1 h prior to STING activation. As previously reported, we observed paradoxical autophosphorylation of TBK1 in the presence of WEHI-112 and MRT67307 (Louis et al, 2019), but a loss of DMXAA-induced p-IRF3 (Figure S3A). Interestingly, in the presence of TBK1/IKKε kinase inhibition, we still observed increased p-p65 levels, although reduced relative to Ctrl-treated BMDMs (Figure S3A).…”

Section: Sting-induced Nf-kb Responses Are Less Sensitive To Tbk1 and Ikkε Kinase Inhibition Than Type I Ifnsmentioning

confidence: 99%

TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-kB (NF-kB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-kB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IkB kinase ε (IKKε) to drive NF-kB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-kB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity.

show abstract

“…Studies using gene-targeted mice have highlighted the nonredundant role of the inducible costimulatory molecule (ICOS), CD40, and lymphotoxin in the initiation and maintenance of GC niches [158]. In GC, follicular T helper (TF H ) cells and B cells cooperate to mediate Ig class switching, affinity selection, generation of memory B cells, and antibody secreting plasma cells [159] (Figure 2). Various signaling molecules (for example, ICOS, CD40-CD40L, and signaling lymphocyte activation molecule- (SLAM-) associated protein (SAP)) are reported to be involved in TF H cell-B cell interactions in the GCs.…”

Section: Natural and Pathogenic Autoantibodiesmentioning

confidence: 99%

Autoantibodies as Diagnostic Markers and Mediator of Joint Inflammation in Arthritis

Fang

Nandakumar

2019

Mediators of Inflammation

View full text Add to dashboard Cite

Rheumatoid arthritis is a systemic, polygenic, and multifactorial syndrome characterized by erosive polyarthritis, damage to joint architecture, and presence of autoantibodies against several self-structures in the serum and synovial fluid. These autoantibodies (anticitrullinated protein/peptide antibodies (ACPAs), rheumatoid factors (RF), anticollagen type II antibodies, antiglucose-6 phosphate isomerase antibodies, anticarbamylated protein antibodies, and antiacetylated protein antibodies) have different characteristics, diagnostic/prognostic value, and pathological significance in RA patients. Some of these antibodies are present in the patients' serum several years before the onset of clinical disease. Various genetic and environmental factors are associated with autoantibody production against different autoantigenic targets. Both the activating and inhibitory FcγRs and the activation of different complement cascades contribute to the downstream effector functions in the antibody-mediated disease pathology. Interplay between several molecules (cytokines, chemokines, proteases, and inflammatory mediators) culminates in causing damage to the articular cartilage and bones. In addition, autoantibodies are proven to be useful disease markers for RA, and different diagnostic tools are being developed for early diagnosis of the clinical disease. Recently, a direct link was proposed between the presence of autoantibodies and bone erosion as well as in the induction of pain. In this review, the diagnostic value of autoantibodies, their synthesis and function as a mediator of joint inflammation, and the significance of IgG-Fc glycosylation are discussed.

show abstract

Therapeutic Effects of a TANK‐Binding Kinase 1 Inhibitor in Germinal Center–Driven Collagen‐Induced Arthritis

Cited by 17 publications

References 56 publications

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

TBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells

Autoantibodies as Diagnostic Markers and Mediator of Joint Inflammation in Arthritis

Contact Info

Product

Resources

About