Dong Wei, Li Yucheng, Fei Qiaoman, Li Senyang, He Xinrui, Chai Yichao, Zhou Junyi, Zong Yujin, Geng Jing, Li Zongfang
National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
Theranostics. 2025 Mar 18;15(10):4416-4445. doi: 10.7150/thno.111116. eCollection 2025.
The spleen, the largest lymphatic organ, comprises a diverse array of immunocytes in approximately one quarter of the body, including T cells, B cells, natural killer cells, and myeloid cells (such as dendritic cells, neutrophils, myeloid-derived suppressor cells, and macrophages). These immune cells undergo dynamic transitions and mobilization, enabling the spleen to execute a wide range of immunological functions. The spleen's structural organization and multicellular composition, along with its reservoir of lymphocytes, facilitate the capture and clearance of blood-borne antigens while also orchestrating both innate and adaptive immune responses. Additionally, the spleen plays critical roles in hematopoiesis and the removal of aged or damaged red blood cells. Despite being innervated by sympathetic (catecholaminergic) nerve fibers, the spleen lacks parasympathetic (vagal or cholinergic) innervation. The neuroimmune axis, particularly the interplay between sympathetic and parasympathetic nervous system immune circuits, significantly influences disease onset and progression. Extensive research employing physical, genetic, and pharmacological approaches has sought to directly modulate splenic immunocytes and activate neuroimmune interactions to restore immune homeostasis and counteract disease. Two primary mechanisms underlie these immunomodulatory interventions: (1) the cholinergic anti-inflammatory pathway, wherein norepinephrine released by splenic catecholaminergic fibers binds to β2-adrenergic receptors on CD4⁺ T cells, triggering acetylcholine secretion, which in turn suppresses inflammatory cytokine production in macrophages via α7 nicotinic acetylcholine receptor signaling, and (2) direct immunomodulation of splenic immunocytes, which regulates key genes and signaling pathways, alters cytokine secretion, and modulates ion flux to influence cellular functions. Among various therapeutic strategies, physical methods, particularly electrical stimulation and splenic ultrasound stimulation, have demonstrated the greatest promise for clinical applications in splenic immunomodulation and disease management.
脾脏是最大的淋巴器官，约占人体重量的四分之一，包含多种免疫细胞，包括T细胞、B细胞、自然杀伤细胞和髓样细胞（如树突状细胞、中性粒细胞、髓源性抑制细胞和巨噬细胞）。这些免疫细胞经历动态转变和动员，使脾脏能够执行广泛的免疫功能。脾脏的结构组织和多细胞组成，以及其淋巴细胞库，有助于捕获和清除血源性抗原，同时协调先天免疫和适应性免疫反应。此外，脾脏在造血以及清除衰老或受损红细胞方面发挥着关键作用。尽管脾脏受交感（儿茶酚胺能）神经纤维支配，但缺乏副交感（迷走或胆碱能）神经支配。神经免疫轴，特别是交感神经系统和副交感神经系统免疫回路之间的相互作用，对疾病的发生和发展有显著影响。广泛的研究采用物理、遗传和药理学方法，试图直接调节脾脏免疫细胞并激活神经免疫相互作用，以恢复免疫稳态并对抗疾病。这些免疫调节干预措施有两个主要机制：（1）胆碱能抗炎途径，其中脾脏儿茶酚胺能纤维释放的去甲肾上腺素与CD4⁺T细胞上的β2-肾上腺素能受体结合，触发乙酰胆碱分泌，进而通过α7烟碱型乙酰胆碱受体信号抑制巨噬细胞中炎性细胞因子的产生；（2）对脾脏免疫细胞的直接免疫调节，调节关键基因和信号通路，改变细胞因子分泌，并调节离子通量以影响细胞功能。在各种治疗策略中，物理方法，特别是电刺激和脾脏超声刺激，在脾脏免疫调节和疾病管理的临床应用中显示出最大的前景。
