Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation.

Kerstin Dürholz,Leona Ehnes,Mathias Linnerbauer,Eva Schmid,Heike Danzer,Michael Hinzpeter-Schmidt,Lena Lößlein,Lena Amend,Michael Frech,Vugar Azizov,Fabian Schälter,Arne Gessner,Sébastien Lucas,Till-Robin Lesker,R Verena Taudte,Jörg Hofmann,Felix Beyer,Hadar Bootz-Maoz,Yasmin Reich,Hadar Romano,Daniele Mauro,Ruth Beckervordersandforth,Maja Skov Kragsnaes,Torkell Ellingsen,Wei Xiang,Aiden Haghikia,Cezmi A Akdis,Francesco Ciccia,Tobias Bäuerle,Kerstin Sarter,Till Strowig,Nissan Yissachar,Georg Schett,Veit Rothhammer,Mario M Zaiss
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Abstract

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid (SCFA) propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.
肠道特异性组胺3受体信号调控小胶质细胞依赖性外周炎症的消退。
慢性炎症性疾病,如类风湿关节炎(RA)已被描述为引起中枢神经系统(CNS)激活。对于使中枢神经系统抑制RA周围炎症的环境因素知之甚少。在这里,我们确定肠道微生物来源的组胺是这样的因素。我们发现,低水平的组胺可以激活肠道神经系统,增加脊髓中抑制性神经递质浓度,恢复体内平衡的小胶质细胞,从而减少关节炎症。肠道中的选择性组胺3受体(H3R)信号传导对这种效果至关重要,因为全身和鞘内应用没有显示出效果。小胶质细胞耗竭或局部神经纤维的药物沉默损害口服H3R激动剂诱导的关节炎促缓解作用。此外,治疗性补充丙酸短链脂肪酸(SCFA)确定了一种增加小鼠和人类肠道局部组胺浓度的方法。因此,我们定义了肠道-中枢-关节轴途径,其中微生物源性组胺通过中枢神经系统启动关节炎的解决。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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