Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
Front Immunol. 2018 Sep 19;9:2118. doi: 10.3389/fimmu.2018.02118. eCollection 2018.
Chemokine synergy-inducing molecules are emerging as regulating factors in cell migration. The alarmin HMGB1, in its reduced form, can complex with CXCL12 enhancing its activity on monocytes via the chemokine receptor CXCR4, while the form containing a disulfide bond, by binding to TLR2 or TLR4, initiates a cascade of events leading to production of cytokines and chemokines. So far, the possibility that the CXCL12/HMGB1 heterocomplex could be maintained in chronic inflammation was debated, due to the release of reactive oxygen species. Therefore, we have assessed if the heterocomplex could remain active in Rheumatoid Arthritis (RA) and its relevance in the disease assessment. Monocytes from RA patients with active disease require a low concentration of HMGB1 to enhance CXCL12-induced migration, in comparison to monocytes from patients in clinical remission or healthy donors. The activity of the heterocomplex depends on disease activity, on the COX2 and JAK/STAT pathways, and is determined by the redox potential of the microenvironment. In RA, the presence of an active thioredoxin system correlates with the enhanced cell migration, and with the presence of the heterocomplex in the synovial fluid. The present study highlights how, in an unbalanced microenvironment, the activity of the thioredoxin system plays a crucial role in sustaining inflammation. Prostaglandin E2 stimulation of monocytes from healthy donors is sufficient to recapitulate the response observed in patients with active RA. The activation of mechanisms counteracting the oxidative stress in the extracellular compartment preserves HMGB1 in its reduced form, and contributes to fuel the influx of inflammatory cells. Targeting the heterocomplex formation and its activity could thus be an additional tool for dampening the inflammation sustained by cell recruitment, for those patients with chronic inflammatory conditions who poorly respond to current therapies.
趋化因子协同诱导分子正在成为细胞迁移的调节因子。其低分子形式的警报素 HMGB1 可以与 CXCL12 形成复合物，通过趋化因子受体 CXCR4 增强其对单核细胞的活性，而含有二硫键的形式通过与 TLR2 或 TLR4 结合，启动一系列事件，导致细胞因子和趋化因子的产生。到目前为止，由于活性氧的释放，CXCL12/HMGB1 异源复合物是否能在慢性炎症中维持的可能性一直存在争议。因此，我们评估了异源复合物在类风湿关节炎（RA）中是否能保持活性及其在疾病评估中的相关性。与处于临床缓解期或健康供体的单核细胞相比，处于活动期的 RA 患者的单核细胞需要较低浓度的 HMGB1 来增强 CXCL12 诱导的迁移。异源复合物的活性取决于疾病的活动度、COX2 和 JAK/STAT 途径，并且由微环境的氧化还原电位决定。在 RA 中，活性硫氧还蛋白系统的存在与增强的细胞迁移以及滑液中异源复合物的存在相关。本研究强调了在不平衡的微环境中，硫氧还蛋白系统的活性如何在维持炎症中发挥关键作用。来自健康供体的单核细胞中前列腺素 E2 的刺激足以重现观察到的处于活动期 RA 患者的反应。细胞外区室中对抗氧化应激的机制的激活将 HMGB1 保持在还原形式，有助于为炎症细胞的流入提供燃料。因此，针对异源复合物的形成及其活性可能是一种额外的工具，可以抑制由细胞募集维持的炎症，对于那些对当前治疗反应不佳的慢性炎症患者。
