The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner
The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner
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DOI：
10.3389/fitd.2023.1334705
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发表时间：
2024-01
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通讯作者：
M. Harnett;J. Doonan;Anuradha Tarafdar;M. Pineda;Josephine Duncombe-Moore;Geraldine Buitrago;Piaopiao Pan;P. Hoskisson;Colin Selman;W. Harnett
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作者：
M. Harnett;J. Doonan;Anuradha Tarafdar;M. Pineda;Josephine Duncombe-Moore;Geraldine Buitrago;Piaopiao Pan;P. Hoskisson;Colin Selman;W. Harnett
寄生虫衍生的免疫调节剂ES-62可以挽救产生IL-10的调节性B细胞(Bregs)的缺陷水平，并抑制慢性Th1/Th17驱动的炎症，以保护类风湿性关节炎(CIA)小鼠的关节免受破坏。这种自身免疫性关节炎还与肠道微生物区系失调和肠道屏障完整性破坏有关。我们最近进一步开发了CIA模型，表明ES-62‘S预防关节破坏与保护肠道屏障完整性和肠道微生物区系正常化有关，从而抑制了CIA小鼠在自身免疫和关节损伤发生之前的肠道病理。由于肠道微生物区系的状况通过影响造血而影响免疫反应，因此我们研究了ES-62是否利用调节肠道-骨髓(BM)轴的动态平衡机制来解决CIA中促进自身免疫和关节破坏的慢性炎症。反映这一点的是，ES-62被发现可以抵消通常与慢性炎症和感染有关的骨髓髓样/淋巴样偏向。这主要是通过ES-62的作用来维持在幼稚、健康的小鼠中观察到的淋巴谱系(B220+和CD3+细胞)的水平，但从CIA小鼠的骨髓中消失。此外，ES-62‘S阻止破骨细胞生成的作用与其抑制CIA诱导的骨髓破骨细胞前体细胞(OCP)上调有关。关键的是，支持ES-62‘S对肠道-骨髓轴的靶向，这种炎性造血的重新连接在微生物群枯竭的小鼠中丢失了。突显ES-62‘S在恢复稳态造血中的重要性的是，在CIA小鼠中，B和T淋巴样细胞的BM水平与关节损伤的严重程度呈负相关，而OCPs的水平呈正相关。
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.