Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase

Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.疼痛敏感性增强是诸多临床疾病常见的共病症，但其潜在致病机制仍未明晰。近期有研究表明，经处理诱导外周组织慢性炎症的啮齿类动物，其慢性痛觉超敏与吲哚胺2,3-双加氧酶（indoleamine 2,3 dioxygenase, IDO）介导的脑内色氨酸分解代谢增强存在关联。本研究显示，急性甲型流感病毒（influenza A virus, IAV）与慢性鼠白血病逆转录病毒（murine leukemia retrovirus, MuLV）感染——二者可分别在肺组织与淋巴组织中强力诱导IDO表达——分别诱发急性与慢性痛觉超敏。与之形成对照的是，IDO1基因完整缺失的小鼠并未出现病毒诱导的痛觉超敏。随着MuLV感染进展，脾脏IDO活性显著升高，但脑与脊髓（中枢神经系统，central nervous system, CNS）组织中IDO1的表达并无明显上调。此外，由表达IDO的细胞产生的色氨酸分解代谢产物犬尿氨酸（kynurenine, Kyn），可在未感染的IDO1缺陷小鼠中诱发痛觉超敏，且能够增强MuLV感染所致的痛觉超敏。MuLV感染可选择性诱导同时表达B细胞标志物（CD19）与树突状细胞标志物（CD11c）的脾脏细胞亚群（CD19+树突状细胞，CD19+ DCs）表达IDO。相较于B细胞或常规（CD19阴性）树突状细胞，CD19+ DCs更易被MuLV感染；自MuLV感染早期阶段起，其增殖速度便快于B细胞，且与常规（CD19阴性）树突状细胞不同，它们呈现出成熟抗原呈递细胞（antigen presenting cell, APC）表型。此外，在体外与体内实验中，与CD4 T细胞的相互作用对于维持CD19+ DCs的功能性IDO表达均为必需。来自MuLV感染且IDO1功能完整的小鼠的脾细胞，可在未感染的IDO1缺陷受体小鼠中诱发痛觉超敏；而在体内选择性耗竭树突状细胞，可减轻MuLV感染的IDO1功能完整小鼠的痛觉超敏，并快速逆转脾肿大——这是MuLV免疫致病的标志性特征。上述发现揭示了表达IDO的CD19+ DCs在宿主抗MuLV感染的免疫应答中发挥关键作用，该作用可增强痛觉超敏并引发免疫病理损伤。综上，本研究结果支持如下假说：病毒感染所致非中枢神经系统内IDO活性升高，可通过犬尿氨酸介导痛觉超敏。宿主抗病毒免疫应答与疼痛敏感性之间此前未被认知的关联提示，IDO抑制剂或可缓解感染期间的疼痛敏感性亢进症状。