Axial spondyloarthritis: emerging drug targets

Cherqaoui, Bilade; Araujo, Luiza M.; Glatigny, Simon; Bréban, Maxime

doi:10.1080/14728222.2021.1973429

Cited by 3 publications

(3 citation statements)

References 118 publications

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“…As in the B27-rat, SpA patients display a Th17 bias that appears to be of critically importance, as confirmed by the efficacy of anti–IL-17 antibodies treatment in a significant number of patients ( 50 , 51 ). Thus, our observation of a similarly decreased STAT1 expression and STAT1 / STAT3 imbalance in Tn from HLA-B27 + SpA patients supports the relevance of this observation to human SpA development.…”

Section: Discussionmentioning

confidence: 77%

STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

Cherqaoui,

Crémazy,

Lauraine

et al. 2023

Front. Immunol.

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IntroductionIn spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27/human β2-microglobulin transgenic rat (B27-rat).MethodsTo investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4+ T cells (Tn). ResultsWe observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1/STAT3 transcription factors activity. Stat1 mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas Stat3/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, STAT1 mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation. DiscussionAltogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4+ T cells in SpA patients, thus offering new clues to better understand and treat SpA.

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Section: Discussionmentioning

confidence: 77%

STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

Cherqaoui,

Crémazy,

Lauraine

et al. 2023

Front. Immunol.

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“…Interestingly, this gene codes for c-maf, a positive regulator of IL-10 production and may thereby inhibit Th 17 response ( 34 ). STAT3 dysfunction has been described in various chronic inflammatory diseases and JAK-STAT inhibitors are effective in treating several of these disorders, including SpA ( 35 , 36 ). The foregoing RNAseq analysis suggested that the inhibitory effect of IL-27 on IL-17 production was associated with STAT3 pathway down-regulation.…”

Section: Resultsmentioning

confidence: 99%

“…Therapeutic options to treat SpA, a disabling chronic inflammatory disorder of the joint, are still limited despite recent advances that include the development of TNF-α, IL-17 and JAK inhibitory agents ( 36 , 39 ). This is why B27-rat, considered as the most faithful animal model of SpA, is highly valuable in understanding the mechanisms of SpA and identifying new therapeutic targets ( 5 , 40 ).This model was instrumental in highlighting CD4 + Th 17 cells and heightened IL-17 production as major components of SpA pathophysiology ( 11 , 36 , 41 ). Moreover, B27-rat DCs exhibit aberrant features, including a decreased production of IFN-γ, IL-10 and IL-27, that could contribute to such deregulated CD4 + T cells phenotype ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Interleukin 27 is a novel cytokine with anti-inflammatory effects against spondyloarthritis through the suppression of Th17 responses

Jouhault

Cherqaoui²,

Jobart-Malfait³

et al. 2023

Front. Immunol.

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IntroductionSpondylarthritis (SpA) development in HLA-B27/human β2-microglobulin transgenic rat (B27-rat) is correlated with altered conventional dendritic cell (cDC) function that promotes an inflammatory pattern of CD4+T cells, including a biased expansion of pro-inflammatory Th17 population and imbalance of regulatory T cells cytokine profile. Transcriptomic analysis revealed that cDCs from B27-rats under express IL-27, an anti-inflammatory cytokine which induces the differentiation of IL-10+ regulatory T cells and inhibits Th17 cells.MethodsHere, we first investigated whether in vitro addition of exogenous IL-27 could reverse the inflammatory pattern observed in CD4+ T cells. Next, we performed preclinical assay using IL-27 to investigate whether in vivo treatment could prevent SpA development in B27-rats.Resultsin vitro addition of IL-27 to cocultures of cDCs and CD4+ T cell subsets from B27-rats reduced IL-17 and enhanced IL-10 production by T cells. Likewise, IL-27 inhibited the production of IL-17 by CD4+ T cells from SpA patients. Interestingly, in vivo treatment with recombinant IL-27 starting before SpA onset, inhibited SpA development in B27-rats through the suppression of IL-17/TNF producing CD4+ T cells.DiscussionOverall, our results reveal a potent inhibitory effect of IL-27 and highlight this cytokine as a promising new therapeutic target in SpA, especially for SpA patients non responders to currently approved biotherapies.

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Knowledge mapping of biological disease-modifying anti-rheumatic drugs for axial spondyloarthritis: a bibliometric study

Chen

Liao

et al. 2023

Clin Rheumatol

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Axial spondyloarthritis: emerging drug targets

Cited by 3 publications

References 118 publications

STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

Interleukin 27 is a novel cytokine with anti-inflammatory effects against spondyloarthritis through the suppression of Th17 responses

Knowledge mapping of biological disease-modifying anti-rheumatic drugs for axial spondyloarthritis: a bibliometric study

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