High salt diet potentiation of AngII HTN : Novel role for Th17 cell infiltration into the PVN

摘要 高血压（HTN）是一种常见的心血管疾病，也是其他心血管疾病的主要危险因素。 疾病尽管在预防和治疗方面取得了进展，但仍有约20%的患者对目前的药物耐药或难治。 治疗。在大多数情况下，治疗抵抗性HTN（HTN）是强烈的“神经源性”，伴随着 交感神经活动（SNA）增强，并与肾素-血管紧张素系统（RAS）和免疫相关 系统激活。如果不及时治疗，神经源性高血压可导致多种合并症， 如中风、痴呆、糖尿病、肾病、阻塞性睡眠呼吸暂停和神经系统疾病， 老年痴呆症虽然神经源性HTN的研究报告了控制SNA的大脑区域的炎症， 驱动前交感神经元活动过度的具体机制尚未被确定。盐敏感 HTN的特征是增加饮食盐后神经元特性发生显著变化 摄入量，最重要的是，在血压升高之前。我们最近的研究表明， 中枢炎症机制导致关键自主脑区神经元的分子改变， 就像下丘脑。更具体地说，我们发现，适度高盐饮食（2%）激活骨髓 （BM）来源的表达IL17 α的CD4+免疫细胞（IC），其单独能够增加血液中的 压力（BP）。这与CD4 + IC的浸润和小胶质细胞的激活有关。 下丘脑室旁核（PVN），以及PVN中的特定分子变化， 可能作为交感神经控制神经元的有效致敏剂，长期以来被认为是过度SNA的驱动因素， 盐敏感性HTN时，血管紧张素II（Ang II）的挑战。因此，该模型提供了几个概念 在阐明神经炎症依赖性神经源性HTN的早期机制方面具有优势，因为我们 能够研究HTN发展之前神经元变化的早期机制。我们的新假设 集中在盐激活的表达IL 17 α的IC的浸润和 PVN前交感神经元对Ang II的过度放电。我们假设免疫驱动 适应强烈地反映了由核因子κ B（NF-kB）驱动的转录活性，核因子κ B是一种主要的 由促炎细胞因子激活的转录因子，包括IL-17 a和小胶质细胞源性 TNF α。这导致SNA的增加，并促进HTN的建立，不仅通过神经源性 血管收缩，但也通过刺激β 1/β 2肾上腺素受体介导的BM IC的持续释放 在BM中激活。结果将告知未来新疗法的发展，以更好地管理 神经源性HTN，并有可能扩展到推进其他盐加重的自身免疫性疾病的治疗。 疾病如结肠炎、银屑病关节炎和系统性红斑狼疮。

Abstract Hypertension (HTN) is a prevalent cardiovascular condition and a leading risk factor for other cardiovascular diseases. Despite advances in prevention and therapy, ~20% of patients are resistant or refractory to current treatments. In most cases, treatment-resistant HTN (HTN) is strongly `neurogenic', being accompanied by exaggerated sympathetic nerve activity (SNA) and linked with renin-angiotensin system (RAS) and immune system activation. If it remains untreated, neurogenic hypertension can lead to numerous comorbidities such as stroke, dementia, diabetes, kidney disease, obstructive sleep apnea, and neurological disorders such as Alzheimer's disease. While studies of neurogenic HTN report inflammation in brain regions that control SNA, specific mechanisms driving hyperactivity of pre-sympathetic neurons have not been identified. Salt-sensitive HTN has been characterized by significant changes in neuronal properties following increased dietary salt intake and, most importantly, prior to blood pressure increase. Our recent work indicates that peripheral and central inflammatory mechanisms lead to molecular alterations in neurons in key autonomic brain regions such as the hypothalamus. More specifically, we found that moderately high salt diet (2%) activates bone marrow (BM)-derived IL17a-expressing CD4+ immune cells (ICs), which alone are capable of increasing blood pressure (BP). This was associated with infiltration of CD4+ ICs and activation of microglia in the paraventricular nucleus (PVN) of the hypothalamus, as well as with specific molecular changes in the PVN that may act as potent sensitizers of sympathetic control neurons, long implicated as drivers of exaggerated SNA in salt-sensitive HTN when challenged by angiotensin II (Ang II). Thus, this model provides several conceptual advantages in elucidation of early mechanisms of neuroinflammation-dependent neurogenic HTN, as we are able to investigate early mechanisms of neuronal changes prior to development of HTN. Our novel hypothesis is focused on the establishment of connection between infiltration of salt-activated IL17a-expressing ICs and exaggerated discharge of PVN pre-sympathetic neurons to Ang II. We postulate that the immune-driven adaptations strongly reflect transcriptional activity driven by nuclear factor kappa B (NF-kB), a major transcriptional factor activated by pro-inflammatory cytokines, including the IL-17a and microglial-derived TNFα. This results in the increase of SNA and promotes establishment of HTN not only through neurogenic vasoconstriction but also by stimulating continued release of BM ICs mediated by β1/β2 adrenoceptor activation in the BM. Outcomes will inform the future development of novel therapeutics to better manage neurogenic HTN, and potentially will extend to advance the treatment of other salt-exacerbated autoimmune disorders such as colitis, psoriatic arthritis and systemic lupus erythematosus.