A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis

Wilde, Katelijne De; Martens, Arne; Lambrecht, Stijn; Jacques, Peggy; Drennan, Michael; Debusschere, Karlijn; Govindarajan, Srinath; Coudenys, Julie; Verheugen, Eveline; Windels, Fien; Catrysse, Leen; Lories, Rik; McGonagle, Dennis; Beyaert, Rudi; Loo, Geert; Elewaut, Dirk

doi:10.1136/annrheumdis-2016-209454

Cited by 64 publications

(58 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Finally, we performed therapeutic dosing experiments with treatment starting at 4 weeks, when arthritis is fulminant ( Figure 2F). For this set of experiments, we included tofacitinib as a control, at a dose commonly reported in the literature (35). There was a reduction in clinical scoring with NDI-031407 treatment, albeit predictably not as strong as in those with tofacitinib treatment.…”

Section: Ndi-031407 Controls Type 3 Immune Cell Activity With Systemimentioning

confidence: 99%

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

Gracey

Hromadová

Lim

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

Section: Ndi-031407 Controls Type 3 Immune Cell Activity With Systemimentioning

confidence: 99%

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

Gracey

Hromadová

Lim

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…Prior psoriasis studies on markers of local inflammation which are associated with an increased risk of CVD include myeloperoxidase, a pro-inflammatory heme protein released by myeloid cells (most likely released into circulation by MPO-producing skin-infiltrating myeloid cells), and resistin, an adipose-tissue derived hormone (most likely from adipose tissue subjacent to psoriasis plaques) [21][22][23][24][25]. In addition, we and others demonstrated that myeloid cells are altered in psoriasis patients, where the number of monocyte-derived suppressor cells (MDSCs) and intermediate (CD14 + CD16 + ) monocytes are increased in psoriasis patients, potentially as a result of similarly disordered myeloid cell release [24,[26][27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Psoriasis and Psoriatic Arthritis Cardiovascular Disease Endotypes Identified by Red Blood Cell Distribution Width and Mean Platelet Volume

Conic

Damiani

Schrom

et al. 2020

JCM

View full text Add to dashboard Cite

In a subset of psoriasis (PsO) and psoriatic arthritis (PsA) patients, the skin and/or joint lesions appear to generate biologically significant systemic inflammation. Red cell distribution width (RDW) and mean platelet volume (MPV) are readily available clinical tests that reflect responses of the bone marrow and/or plasma thrombogenicity (e.g., inflammation), and can be markers for major adverse cardiac events (MACE). We aimed to evaluate if RDW and MPV may be employed as inexpensive, routinely obtained biomarkers in predicting myocardial infarction (MI), atrial fibrillation (AF), and chronic heart failure (CHF) in psoriatic and psoriatic arthritis patients. The study was divided into two parts: (a) case control study employing big data (Explorys) to assess MPV and RDW in psoriasis, psoriatic arthritis and control cohorts; (b) a clinical observational study to validate the predictive value of RDW and to evaluate RDW response to anti-psoriatic therapies. We used Explorys, an aggregate electronic database, to identify psoriatic patients with available MPV and RDW data and compared them to gender and age matched controls. The incidence of myocardial infarction (MI), atrial fibrillation (AF), and chronic heart failure (CHF) was highest among patients with both elevated RDW and MPV, followed by patients with high RDW and normal MPV. RDW elevation among PsA patients was associated with an increased risk of MI, AF, and CHF. In a local clinical cohort, high RDWs were concentrated in a subset of patients who also had elevated circulating resistin levels. Among a small subset of participants who were treated with various systemic and biologic therapies, and observed over a year, and in whom RDW was elevated at baseline, a sustained response to therapy was associated with a decrease in RDW. RDW and MPV, tests commonly contained within routine complete blood count (CBC), may be a cost-effective manner to identify PsO and PsA patients at increased risk of MACE.

show abstract

“…Inhibition of JAK1 and JAK3 kinase activity by the clinically applied JAK inhibitor tofacitinib prevented IL-17A expression in anti-TNF-treated eff Treg, suggesting that TNFα signaling is involved in driving JAK/STAT signaling. Although TNFα is not a prototypic JAK/STAT activating cytokine, the anti-inflammatory molecule A20 (encoded by TNFAIP3) that is a downstream target of TNFα signaling acts as a regulator of STAT (67,68). The absence of A20 in myeloid cells resulted in enhanced STAT1dependent inflammation (68).…”

Section: Discussionmentioning

confidence: 99%

“…Although TNFα is not a prototypic JAK/STAT activating cytokine, the anti-inflammatory molecule A20 (encoded by TNFAIP3) that is a downstream target of TNFα signaling acts as a regulator of STAT (67,68). The absence of A20 in myeloid cells resulted in enhanced STAT1dependent inflammation (68). This relationship needs to be confirmed in eff Treg.…”

Section: Discussionmentioning

confidence: 99%

TNFα-Signaling Modulates the Kinase Activity of Human Effector Treg and Regulates IL-17A Expression

Urbano

Heeswijk

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

Maintenance of regulatory T cells CD4 + CD25 high FOXP3 + (Treg) stability is vital for proper Treg function and controlling the immune equilibrium. Treg cells are heterogeneous and can reveal plasticity, exemplified by their potential to express IL-17A. TNFα-TNFR2 signaling controls IL-17A expression in conventional T cells via the anti-inflammatory ubiquitin-editing and kinase activity regulating enzyme TNFAIP3/A20 (tumor necrosis factor-alpha-induced protein 3). To obtain a molecular understanding of TNFα signaling on IL-17 expression in the human effector (eff Treg, CD25 high CD45RA −) Treg subset, we here studied the kinome activity regulation by TNFα signaling. Using FACS-sorted naïve (naïve Treg, CD25 high CD45RA +) and eff Treg subsets, we demonstrated a reciprocal relationship between TNFα and IL-17A expression; eff Treg (TNFα low /IL-17A high) and naïve Treg (TNFα high /IL-17A low). In eff Treg, TNFα-TNFR2 signaling prevented IL-17A expression, whereas inhibition of TNFα signaling by clinically applied anti-TNF antibodies led to increased IL-17A expression. Inhibition of TNFα signaling led to reduced TNFAIP3 expression, which, by using siRNA inhibition of TNFAIP3, appeared causally linked to increased IL-17A expression in eff Treg. Kinome activity screening of CD3/CD28-activated eff Treg revealed that anti-TNF-mediated neutralization led to increased kinase activity. STRING association analysis revealed that the TNF suppression eff Treg kinase activity network was strongly associated with kinases involved in TCR, JAK, MAPK, and PKC pathway signaling. Small-molecule-based inhibition of TCR and JAK pathways prevented the IL-17 expression in eff Treg. Together, these findings stress the importance of TNF-TNFR2 in regulating the kinase architecture of antigen-activated eff Treg and controlling IL-17 expression of the human Treg. These findings might be relevant for optimizing anti-TNF-based therapy and may aid in preventing Treg plasticity in case of Treg-based cell therapy.

show abstract

A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis

Cited by 64 publications

References 27 publications

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

Psoriasis and Psoriatic Arthritis Cardiovascular Disease Endotypes Identified by Red Blood Cell Distribution Width and Mean Platelet Volume

TNFα-Signaling Modulates the Kinase Activity of Human Effector Treg and Regulates IL-17A Expression

Contact Info

Product

Resources

About