Toll-Like Receptors, Infections, and Rheumatoid Arthritis

Arleevskaya, Marina I; Larionova, Regina; Brooks, Wesley H.; Bettacchioli, Éléonore; Renaudineau, Yves

doi:10.1007/s12016-019-08742-z

Cited by 81 publications

(49 citation statements)

References 82 publications

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“…5a). Moreover, and perhaps consistent with the proposed pro-inflammatory roles of TLR signalling in CIA/RA pathogenesis 42, 43 , LPS/TLR4 signalling substantially increases miR-155 levels in naïve SFs and this increase is associated with similar kinetics of MyD88 and IL-6 (although not Traf6) upregulation, at the mRNA level (Fig. 5b).…”

Section: Resultssupporting

confidence: 81%

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

Corbet

Pineda

Yang

et al. 2020

Preprint

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The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an “aggressive” pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted “safe” phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct “protective” phenotype. Such unique behaviour signposts potential DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA.

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Section: Resultssupporting

confidence: 81%

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

Corbet

Pineda

Yang

et al. 2020

Preprint

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“…Inflammatory processes in RA, such as swelling of the synovium of the joint, with subsequent destruction of articular structures are associated with activation of synovial fibroblasts and Th-lymphocytes [48]. In the last few years, various studies figured out that the manifestation of RA is critically dependent on expression of TLR family members expression, which in turn is acknowledged to play a crucial role in T-lymphocytes function and differentiation [49][50][51]. Previous studies have shown the importance of TLR4 and TLR2 function in the pathogenesis of RA.…”

Section: Discussionmentioning

confidence: 99%

Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Metothrexate in Rats with Adjuvant Arthritis

et al. 2021

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Anti-inflammatory potential of orally administrated bioflavonoid-robinin, active sub-stance of original drug Flaroninum™ (FL), was investigated in the combination with methotrexate (MTX) and in monotherapy in rats suffering from adjuvant-induced arthritis (AA). Robinin (kaempferol-3-O-robinoside-7-O-rhamnoside) was isolated from the aerial parts of Astragalus falcatus Lam. The monotherapy with robinin was not efficient in alleviating symptoms of AA. The combination of MTX with robinin was similarly active as MTX alone in reducing the hind paw volume and change of body weight during the whole experiment. The combination, however, reduced plasma levels of Interleukin-17Aand activity of gamma-glutamyl transferase in joint more efficiently then MTX alone. Our results demonstrate that the novel combination of robinin and MTX mildly improved the reduction of inflammation in experimental arthritis.

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“…Значительную роль в инициации воспаления играет большое семейство Toll-подобных рецепторов, реализующих свои функции в липидных рафтах клеточных мембран. TLRs являются не только первой линией защиты от чужеродных агентов, но и ключевым звеном в активации врожденного и адаптивного иммунного ответа, поэтому могут рассматриваться как важная таргетная мишень для создания новых фармпрепаратов [20]. На сегодняшний день разрабатываются подходы использования антагонистов TLR, основанные на специфическом ингибировании данных рецепторов и супрессии воспаления [70].…”

Section: заключениеunclassified

“…Такая реакция иммунной системы развивается в ответ на постоянно действующие триггерные факторы слабой интенсивности и характеризуется незначительным повышением активности иммунных клеток и уровня провоспалительных цитокинов. Хроническое системное низкоинтенсивное воспаление тесно связано с нарушениями в регуляции TLRs [20].…”

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The role of lipids in the signaling mechanisms of toll-like receptors

et al. 2020

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Toll-like receptors (TLRs) are important players in innate and adaptive immune responses involved in the initiation of the inflammatory process in response to the stimulating influence of endogenous (аllarmine) and exogenous ligands (pathogens viruses, bacteria, fungi). It has now become apparent that not only viral and bacterial infections but non-infectious inflammatory diseases are accompanied by the activation of inflammatory response systems and the development of chronic inflammation associated with disorders in the regulation of the TLRs system. In this regard, the ligand-independent activation of TLRs, which occurs with the participation of lipids, is actively studied. Their signalling functions of TLRs implemented in unique microdomains does membrane lipid rafts that coordinate many cellular processes. The ability to activate TLRs has been found for saturated fatty acids (SFAs), both exogenous and endogenous. On the other hand, TLRs can be inhibited by omega-3 polyunsaturated fatty acids (PUFAs), which can block the inflammatory process. The activation of TLRs triggers a signal cascade that induces the production of reactive oxygen and nitrogen species. The development of oxidative stress is accompanied by the formation of oxidized forms of phospholipids (Ox-PLs), which also induce the development of chronic inflammation. At the same time, Ox-PLs is characterized not only by pro-inflammatory but also anti-inflammatory activity, which necessitates in-depth studies of their role in the implementation of these processes. This review article discusses the mechanisms by which SFAs, PUFAs, and Ox-PLs modulate TLRs activation in lipid rafts. Research into the details of these mechanisms will contribute to the development of a strategy to reduce the risk of chronic diseases caused by inflammatory reactions mediated by TLRs.

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Toll-Like Receptors, Infections, and Rheumatoid Arthritis

Cited by 81 publications

References 82 publications

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Metothrexate in Rats with Adjuvant Arthritis

The role of lipids in the signaling mechanisms of toll-like receptors

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