Engelhart Morgan J, Brock Orion D, Till Jessica M, Glowacki Robert W P, Cantwell Jason W, Clarke David J, Wesener Darryl A, Ahern Philip P
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Microbiol Spectr. 2025 Mar 4;13(3):e0166924. doi: 10.1128/spectrum.01669-24. Epub 2025 Jan 27.
The intestine is home to a complex immune system that is engaged in mutualistic interactions with the microbiome that maintain intestinal homeostasis. A variety of immune-derived anti-inflammatory mediators have been uncovered and shown to be critical for maintaining these beneficial immune-microbiome relationships. Notably, the gut microbiome actively invokes the induction of anti-inflammatory pathways that limit the development of microbiome-targeted inflammatory immune responses. Despite the importance of this microbiome-driven immunomodulation, detailed knowledge of the microbial factors that promote these responses remains limited. We have previously established that the gut symbiont stimulates the production of the anti-inflammatory cytokine IL-10 via soluble factors in a Toll-like receptor 2 (TLR2)-MyD88-dependent manner. Here, using TLR2 activity reporter cell lines, we show that the capacity of to stimulate TLR2 activity was not critically dependent on either of the canonical heterodimeric forms of TLR2, TLR2/TLR1, or TLR2/TLR6, that typically mediate its function. Furthermore, biochemical manipulation of -conditioned media suggests that IL-10 induction is mediated by a protease-resistant or non-proteogenic factor. We next uncovered that deletion of gene , a predicted secreted lipoprotein, significantly impaired the capacity of to induce IL-10, while complementation restored IL-10 induction, suggesting a role for in the immunomodulatory function of . Collectively, these data provide molecular insight into the pathways through which operates to promote intestinal immune tolerance and symbiosis.
Intestinal homeostasis requires the establishment of peaceful interactions between the gut microbiome and the intestinal immune system. Members of the gut microbiome, like the symbiont , actively induce anti-inflammatory immune responses to maintain mutualistic relationships with the host. Despite the importance of such interactions, the specific microbial factors responsible remain largely unknown. Here, we show that , which stimulates Toll-like receptor 2 (TLR2) to drive IL-10 production, can stimulate TLR2 independently of TLR1 or TLR6, the two known TLR that can form heterodimers with TLR2 to mediate TLR2-dependent responses. Furthermore, we show that IL-10 induction is likely mediated by a protease-resistant or non-proteogenic factor, and that this requires gene , a predicted secreted lipoprotein and peptidase. Collectively, our work provides insight into the molecular dialog through which coordinates anti-inflammatory immune responses. This knowledge may facilitate future strategies to promote such responses for therapeutic purposes.
肠道是一个复杂免疫系统的所在地，该系统与维持肠道内稳态的微生物群进行共生相互作用。多种免疫衍生的抗炎介质已被发现，并被证明对维持这些有益的免疫 - 微生物群关系至关重要。值得注意的是，肠道微生物群积极引发抗炎途径的诱导，从而限制针对微生物群的炎症免疫反应的发展。尽管这种微生物群驱动的免疫调节很重要，但促进这些反应的微生物因子的详细知识仍然有限。我们之前已经确定，肠道共生菌通过可溶性因子以Toll样受体2（TLR2）-MyD88依赖性方式刺激抗炎细胞因子IL-10的产生。在这里，使用TLR2活性报告细胞系，我们表明该共生菌刺激TLR2活性的能力并不关键依赖于通常介导其功能的TLR2的两种典型异二聚体形式，即TLR2/TLR1或TLR2/TLR6。此外，对该共生菌条件培养基的生化操作表明，IL-10的诱导是由一种蛋白酶抗性或非蛋白ogenic因子介导的。接下来，我们发现预测的分泌脂蛋白基因的缺失显著损害了该共生菌诱导IL-10的能力，而互补恢复了IL-10的诱导，这表明该基因在该共生菌的免疫调节功能中起作用。总的来说，这些数据提供了关于该共生菌促进肠道免疫耐受和共生的分子途径的见解。
肠道内稳态需要在肠道微生物群和肠道免疫系统之间建立和平的相互作用。肠道微生物群的成员，如共生菌，积极诱导抗炎免疫反应以维持与宿主的共生关系。尽管这种相互作用很重要，但具体负责的微生物因子在很大程度上仍然未知。在这里，我们表明，刺激Toll样受体2（TLR2）以驱动IL-10产生的该共生菌，可以独立于TLR1或TLR6刺激TLR2，TLR1和TLR6是两种已知的可以与TLR2形成异二聚体以介导TLR2依赖性反应的TLR。此外，我们表明IL-10的诱导可能由一种蛋白酶抗性或非蛋白ogenic因子介导，并且这需要基因，一种预测的分泌脂蛋白和肽酶。总的来说，我们的工作提供了关于该共生菌协调抗炎免疫反应的分子对话的见解。这些知识可能有助于未来为治疗目的促进此类反应的策略。
