神经免疫紊乱在特应性皮炎中的作用研究进展

Research progress in neuroimmune disorders in atopic dermatitis

特应性皮炎(atopic dermatitis,AD)是全球发病率最高的慢性炎症性皮肤病,临床主要表现为湿疹样皮肤病变、瘙痒和干皮症。近来有研究发现,AD患者的皮损中的感觉神经元可同时与角质形成细胞(keratinocyte,KC)、免疫细胞异常互作,导致神经免疫紊乱的发生。其中,参与神经免疫紊乱的感觉神经元有2类,包括组胺能感觉神经元和非组胺能感觉神经元。在神经免疫紊乱中,KC和免疫细胞可通过分泌白细胞介素-4(interleukin-4,IL-4)、IL-13、IL-31、IL-33、胸腺基质淋巴细胞生成素等促炎细胞因子以及C-X-C模体趋化因子配体12(C-X-C motif chemokine ligand 12,CXCL12)、CXCL10等趋化因子激活感觉神经元以诱发瘙痒,还可分泌神经生长因子、脑源性神经营养因子和神经鞘胚素等神经肽诱导感觉神经元过度生长,以促进神经免疫互作。同时,感觉神经元过度释放的降钙素基因相关肽和P物质等神经肽可作用于KC和免疫细胞,从而加剧皮肤炎症。近年来,诸多靶向神经免疫紊乱的药物处于临床前研究、临床试验等阶段,或已上市用于AD治疗,其中该课题组发现局麻药物利多卡因可靶向神经免疫紊乱并能够在临床上缓解AD患者的瘙痒及皮肤炎症。目前,神经免疫紊乱在AD中的作用鲜少被系统性讨论。基于此,该文围绕参与神经免疫紊乱的感觉神经元种类,KC、免疫细胞及感觉神经元在神经免疫紊乱中的作用,以及靶向神经免疫紊乱的治疗策略进行综述。

Atopic dermatitis(AD)is a chronic inflammatory skin disease with the highest incidence in the world.The main clinical manifestations are eczema-like skin lesions,pruritus and xeroderma.Recent studies have revealed that sensory neurons in the skin lesions of AD patients can interact abnormally with keratinocytes(KC)and immune cells,leading to neuroimmune disorders.Among them,there are two types of sensory neurons involved in neuroimmune disorders,including histaminergic and nonhistaminergic sensory neurons.In neuroimmune disorders,KC and immune cells activate sensory neurons to induce pruritus by secreting proinflammatory cytokines such as interleukin-4(IL-4),IL-13,IL-31,IL-33,and thymic stromal lymphopoietin,as well as chemokines such as C-X-C motif chemokine ligand 12(CXCL12)and CXCL10.In addition,neuropeptides such as nerve growth factor,brain-derived neurotrophic factor and artemin secreted by KC and immune cells can induce overgrowth of sensory neurons,thereby promoting neuroimmune disorders.At the same time,the excessive release of neuropeptides such as calcitonin gene-related peptide and substance P by sensory neurons can act on KC and immune cells,thereby aggravating skin inflammation.In recent years,many drugs targeting neuroimmune disorders are in preclinical studies,clinical trials and other stages,or have been marketed for the treatment of AD.Among them,our research group has found that lidocaine,a local anesthetic,can target neuroimmune disorders and relieve pruritus and skin inflammation in AD patients.At present,the role of neuroimmune disorders in AD has not been systematically discussed.Based on this,this article reviews the types of sensory neurons involved in neuroimmune disorders,the role of KC,immune cells and sensory neurons in neuroimmune disorders,as well as the therapeutic strategies targeting neuroimmune disorders.