Histamine H3 Receptor Integrates Peripheral Inflammatory Signals in the Neurogenic Control of Immune Responses and Autoimmune Disease Susceptibility

Histamine H3 receptor (Hrh3/H3R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H3R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H3R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H3RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H3R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H3R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression. 8 pooled samples from at least 3 mice per pool组胺H3受体（Histamine H3 receptor，Hrh3/H3R）主要由中枢神经系统（central nervous system，CNS）内的神经元表达，其功能为突触前抑制性自身受体与异源受体。既往研究中，我们发现H3R介导的中枢组分参与实验性自身免疫性脑脊髓炎（experimental allergic encephalomyelitis，EAE，多发性硬化症（multiple sclerosis，MS）的主要自身免疫模型）的易感性，该组分与血脑屏障通透性的神经源性调控及外周T细胞效应应答密切相关。此外，我们确定Hrh3是EAE易感位点Eae8的位置候选基因。本研究首先对EAE易感型SJL小鼠与抵抗型B10.S小鼠之间的Hrh3多态性进行表征，并证实中枢神经系统内的Hrh3亚型表达会以等位基因特异性的方式，受急性外周炎症刺激差异化调控。随后我们发现，免疫组分的任何亚群均不表达Hrh3，且次级淋巴组织在解剖学上处于中枢H3R信号的调控范围内。据此，通过转录组分析我们证实，与野生型（wild type，WT）小鼠相比，H3R基因敲除（H3RKO）小鼠的淋巴结在炎症刺激下呈现独特的转录谱，这表明中枢H3R信号可负向调控外周免疫应答。本研究结果进一步支持了T细胞应答的神经源性调控与中枢自身免疫疾病易感性之间的功能关联，该关联与急性及/或慢性外周炎症同时发生。因此，以H3R为靶点的药理学干预或可用于预防多发性硬化症中新病灶的形成与发展，从而限制疾病进展。每组混合样本至少包含3只小鼠，共制备8组混合样本。