Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China.
Immunity. 2018 Jul 17;49(1):107-119.e4. doi: 10.1016/j.immuni.2018.04.021. Epub 2018 Jun 26.
Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4-expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders.
肠道巨噬细胞对于胃肠道（GI）稳态至关重要，但我们对于其调节肠道蠕动功能的理解尚不完全。在此，我们报告表达趋化因子（C-X3-C 型）受体 1 的肌间巨噬细胞（MMs）对于维持正常 GI 蠕动是必需的。MMs 表达瞬时受体电位香草酸 4（TRPV4）通道，可感知热、机械和化学线索。TRPV4 的选择性药理学抑制或巨噬细胞中 TRPV4 的条件性缺失可降低肠道蠕动，足以逆转与化疗治疗相关的 GI 蠕动过度。从机制上讲，通过 TRPV4 刺激 MMs 可促进前列腺素 E2 的释放，并通过肠平滑肌细胞中的前列腺素 E 受体信号以旁分泌方式引起结肠收缩，而无需肠神经系统的输入。总的来说，我们的数据确定表达 TRPV4 的 MMs 是维持正常 GI 蠕动所必需的重要组成部分，并为 GI 运动障碍提供了潜在的药物靶点。
