Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States.
Front Cell Infect Microbiol. 2021 Sep 10;11:739874. doi: 10.3389/fcimb.2021.739874. eCollection 2021.
The involvement of the enteric nervous system, which is a source of S100B, in () infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from -infected mice. To investigate the role of S100B signaling in expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated mediated expression activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.
肠道神经系统的参与，其是 S100B 的来源，在艰难梭菌感染（CDI）中理解甚少，尽管已知感染后会发生肠道运动功能障碍。在这里，我们研究了 S100B 在 CDI 中的作用，并检查了在毒素 A (TcdA)和 B (TcdB)诱导的肠神经胶质细胞 (EGC)炎症反应中激活的 S100B 信号通路。在有和没有 CDI 的患者的结肠组织和粪便样本中以及感染的小鼠的结肠组织中测量 S100B 的表达。为了研究 S100B 信号在 TcdA 和 TcdB 诱导的 表达中的作用，使用了大鼠 EGC。在 CDI 患者的结肠活检和感染小鼠的结肠组织中发现 S100B 增加。与非 CDI 病例相比，患有 CDI 促发腹泻的患者粪便 S100B 水平更高。用戊脒抑制 S100B 减少了 IL-1β、IL-18、IL-6、GMCSF、TNF-α、IL-17、IL-23 和 IL-2 的合成，并下调了多种 NFκB 相关基因，增加了保护性介质的转录（SOCS2 和 Bcl-2），减少了中性粒细胞的募集，并改善了小鼠的肠道损伤和腹泻严重程度。在 EGC 中，TcdA 和 TcdB 上调了介导的 RAGE/PI3K/NFκB 表达激活。因此，CDI 似乎在 EGC 中上调了结肠 S100B 信号，进而增强了炎症反应。抑制 S100B 活性可减轻由 毒素引起的肠道损伤和腹泻。我们的研究结果为 S100B 在 CDI 发病机制中的作用提供了新的见解，并为治疗干预开辟了新途径。
