NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
Brain Behav Immun. 2023 Aug;112:96-117. doi: 10.1016/j.bbi.2023.06.003. Epub 2023 Jun 5.
Inflammatory bowel disease (IBD) is a chronic condition with a high recurrence rate. To date, the clinical treatment of IBD mainly focuses on inflammation and gastrointestinal symptoms while ignoring the accompanying visceral pain, anxiety, depression, and other emotional symptoms. Evidence is accumulating that bi-directional communication between the gut and the brain is indispensable in the pathophysiology of IBD and its comorbidities. Increasing efforts have been focused on elucidating the central immune mechanisms in visceral hypersensitivity and depression following colitis. The triggering receptors expressed on myeloid cells-1/2 (TREM-1/2) are newly identified receptors that can be expressed on microglia. In particular, TREM-1 acts as an immune and inflammatory response amplifier, while TREM-2 may function as a molecule with a putative antagonist role to TREM-1. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we found that peripheral inflammation induced microglial and glutamatergic neuronal activation in the anterior cingulate cortex (ACC). Microglial ablation mitigated visceral hypersensitivity in the inflammation phase rather than in the remission phase, subsequently preventing the emergence of depressive-like behaviors in the remission phase. Moreover, a further mechanistic study revealed that overexpression of TREM-1 and TREM-2 remarkably aggravated DSS-induced neuropathology. The improved outcome was achieved by modifying the balance of TREM-1 and TREM-2 via genetic and pharmacological means. Specifically, a deficiency of TREM-1 attenuated visceral hyperpathia in the inflammatory phase, and a TREM-2 deficiency improved depression-like symptoms in the remission phase. Taken together, our findings provide insights into mechanism-based therapy for inflammatory disorders and establish that microglial innate immune receptors TREM-1 and TREM-2 may represent a therapeutic target for the treatment of pain and psychological comorbidities associated with chronic inflammatory diseases by modulating neuroinflammatory responses.
炎症性肠病（IBD）是一种具有高复发率的慢性疾病。迄今为止，IBD 的临床治疗主要集中在炎症和胃肠道症状上，而忽略了伴随的内脏疼痛、焦虑、抑郁等情绪症状。有证据表明，肠道和大脑之间的双向通讯在 IBD 及其合并症的病理生理学中是必不可少的。越来越多的人致力于阐明结肠炎后内脏敏感性和抑郁的中枢免疫机制。髓样细胞表达的触发受体-1/2（TREM-1/2）是新发现的可以在小胶质细胞上表达的受体。特别是，TREM-1 作为免疫和炎症反应的放大器，而 TREM-2 可能作为 TREM-1 的潜在拮抗剂发挥作用。在本研究中，我们使用葡聚糖硫酸钠（DSS）诱导的结肠炎模型，发现外周炎症诱导前扣带回皮质（ACC）中小胶质细胞和谷氨酸能神经元的激活。炎症期小胶质细胞消融减轻了内脏高敏性，而在缓解期则没有，随后在缓解期防止了抑郁样行为的出现。此外，进一步的机制研究表明，TREM-1 和 TREM-2 的过表达显著加重了 DSS 诱导的神经病理学。通过遗传和药理学手段改变 TREM-1 和 TREM-2 的平衡，可以改善这种结果。具体来说，TREM-1 缺乏减轻了炎症期的内脏高敏性，而 TREM-2 缺乏改善了缓解期的抑郁样症状。总之，我们的研究结果为炎症性疾病的基于机制的治疗提供了新的见解，并表明小胶质细胞先天免疫受体 TREM-1 和 TREM-2 通过调节神经炎症反应，可能成为治疗与慢性炎症性疾病相关的疼痛和心理合并症的治疗靶点。
