PDF(Pubmed)
Abstract：
The parasitic worm-derived immunomodulator, ES-62 rescues defective levels of IL-10-producing regulatory B cells (Bregs) and suppresses chronic Th1/Th17-driven inflammation to protect against joint destruction in the mouse collagen-induced arthritis (CIA) model of rheumatoid arthritis. Such autoimmune arthritis is also associated with dysbiosis of the gut microbiota and disruption of intestinal barrier integrity. We recently further exploited the CIA model to show that ES-62\'s prevention of joint destruction is associated with protection of intestinal barrier integrity and normalization of the gut microbiota, thereby suppressing the gut pathology that precedes the onset of autoimmunity and joint damage in CIA-mice. As the status of the gut microbiota impacts on immune responses by influencing haematopoiesis, we have therefore investigated whether ES-62 harnesses the homeostatic mechanisms regulating this gut-bone marrow (BM) axis to resolve the chronic inflammation promoting autoimmunity and joint destruction in CIA. Reflecting this, ES-62 was found to counteract the BM myeloid/lymphoid bias typically associated with chronic inflammation and infection. This was achieved primarily by ES-62 acting to maintain the levels of lymphoid lineages (B220+ and CD3+ cells) observed in naïve, healthy mice but lost from the BM of CIA-mice. Moreover, ES-62\'s ability to prevent bone-destroying osteoclastogenesis was found to be associated with its suppression of CIA-induced upregulation of osteoclast progenitors (OCPs) in the BM. Critically, and supporting ES-62\'s targeting of the gut-BM axis, this rewiring of inflammatory haematopoiesis was lost in mice with a depleted microbiome. Underlining the importance of ES-62\'s actions in restoring steady-state haematopoiesis, the BM levels of B and T lymphoid cells were shown to be inversely correlated, whilst the levels of OCPs positively correlated, with the severity of joint damage in CIA-mice.
摘要：
寄生虫来源的免疫调节剂，ES-62挽救了产生IL-10的调节性B细胞（Bregs）的缺陷水平，并抑制了慢性Th1/Th17驱动的炎症，以防止类风湿性关节炎小鼠胶原诱导的关节炎（CIA）模型中的关节破坏。这种自身免疫性关节炎还与肠道微生物群的生态失调和肠道屏障完整性的破坏有关。我们最近进一步利用CIA模型来显示ES-62预防关节破坏与保护肠屏障完整性和肠道微生物群正常化有关。从而抑制CIA小鼠自身免疫和关节损伤发作之前的肠道病理。由于肠道微生物群的状态通过影响造血功能影响免疫反应，因此，我们研究了ES-62是否利用调节该肠-骨髓（BM）轴的稳态机制来解决CIA中促进自身免疫和关节破坏的慢性炎症。反映这一点，发现ES-62可以抵消通常与慢性炎症和感染相关的BM骨髓/淋巴样偏倚。这主要是通过ES-62作用来维持在幼稚中观察到的淋巴谱系（B220和CD3细胞）的水平来实现的。健康的小鼠，但从CIA小鼠的BM中丢失。此外，发现ES-62阻止破坏骨的破骨细胞生成的能力与其抑制CIA诱导的BM中破骨细胞祖细胞（OCP）的上调有关。严重的,并支持ES-62对肠-BM轴的靶向，在微生物组耗尽的小鼠中，这种炎性造血功能的重新连接丢失了。强调ES-62在恢复稳态造血中的作用的重要性，B淋巴细胞和T淋巴细胞的BM水平呈负相关，虽然OCPs的水平呈正相关，与CIA小鼠关节损伤的严重程度有关。
