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首页> 外文期刊>Molecular and Cellular Pediatrics >Myeloid regulatory cells: cross talk of innate and adaptive immunity to maintain the intestinal immune homeostasis in inflammatory bowel disease
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Myeloid regulatory cells: cross talk of innate and adaptive immunity to maintain the intestinal immune homeostasis in inflammatory bowel disease

机译：髓样调节细胞：固有免疫和适应性免疫的相互作用，在炎症性肠病中维持肠道免疫稳态

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Intestinal monocytes/macrophages sustain the intestinal immune homeostasis and might be an attractive therapeutic target for the management of inflammatory bowel disease (IBD). Granulocyte macrophage colony-stimulating factor (GM-CSF) exerts beneficial effects in intestinal inflammation and promotes STAT3-mediated expansion of myeloid-derived suppressor cells (MDSCs). We explored whether GM-CSF mediates its beneficial effects in IBD via myeloid regulatory cells (Mreg).Here we show that GM-CSF i) provokes non-classical monocyte activation; ii) drives monocytes towards an anti-inflammatory phenotype; iii) enhances innate immune functions; iv) primes monocyte responses to secondary microbial stimuli; and v) accelerates epithelial healing via monocytes. GM-CSF-activated monocytes (GMaM) show therapeutic activity in T cell-induced colitis in Rag1-/- mice with increased production of IL-4, IL-10, IL-13 and decreased production of IFNγ in LPMCs. Confirming this finding, GMaM attract T cells and shape their differentiation towards Th2 cells in vitro. In addition, GMaM induce regulatory (Foxp3+) T cells (Treg) in vitro and adoptive transfer of GMaM in chronic DSS-induced colitis ameliorates disease in vivo with accelerated gut homing of GMaM and induction of colonic Treg. Myeloid-cell specific STAT3 activation protects gp130757F/F mice from colitis via MDSC expansion and increased production of suppressive and protective cytokines. LysMcre/STAT3flox mice with myeloid-specific STAT3-deficiency show opposite effects and are not protected from colitis. Additionally, MDSCs of gp130757F/F mice produce significantly more IL-4, IL-10 and IL-13.In summary, beneficial effects of GM-CSF in IBD may possibly be mediated through reprogramming of monocytes and MDSCs via enhanced innate immune functions as well as regulation of adaptive immunity. Our findings support the exploration of stimulating rather than suppressive therapies for patients with IBD and underpin that Mreg might become a promising novel cell-based therapeutic option.
机译：肠道单核细胞/巨噬细胞维持肠道免疫稳态，可能是治疗炎症性肠病（IBD）的有吸引力的治疗靶标。粒细胞巨噬细胞集落刺激因子（GM-CSF）在肠道炎症中发挥有益作用，并促进STAT3介导的髓样抑制细胞（MDSCs）的扩增。我们研究了GM-CSF是否通过髓样调节细胞（Mreg）介导了IBD的有益作用。在这里，我们证明了GM-CSF i）引起了非经典的单核细胞激活。 ii）驱动单核细胞走向抗炎表型; iii）增强先天免疫功能; iv）引发单核细胞对次级微生物刺激的反应; v）通过单核细胞促进上皮愈合。 GM-CSF激活的单核细胞（GMaM）在Rag1-/-小鼠的T细胞诱导的结肠炎中表现出治疗活性，同时在LPMC中增加了IL-4，IL-10，IL-13的产生，并减少了IFNγ的产生。证实这一发现，GMaM在体外吸引T细胞并使其向Th2细胞分化。此外，GMaM可在体外诱导调节性（Foxp3 +）T细胞（Treg），而在慢性DSS诱发的结肠炎中，GMaM的过继转移可改善肠道内的GMaM归巢和诱导结肠Treg，从而改善体内疾病。髓样细胞特异的STAT3激活可通过MDSC扩展并增加抑制性和保护性细胞因子的产生，保护gp130757F / F小鼠免于结肠炎。具有髓样特异性STAT3缺陷的LysMcre / STAT3flox小鼠表现出相反的作用，并且没有受到结肠炎的保护。此外，gp130757F / F小鼠的MDSC产生明显更多的IL-4，IL-10和IL-13。总之，GM-CSF对IBD的有益作用可能是通过增强先天免疫功能，通过单核细胞和MDSC的重编程来介导的。以及适应性免疫的调节。我们的发现支持对IBD患者进行刺激而非抑制疗法的探索，并支持Mreg可能成为有前途的新型基于细胞的治疗选择。

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