Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Japan.
Department of Anesthesiology, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
Int J Mol Sci. 2024 Sep 20;25(18):10107. doi: 10.3390/ijms251810107.
Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that induces cytokine hypersecretion. Receptor activity-modifying protein (RAMP) 1, a subunit of the calcitonin gene-related peptide (CGRP) receptor, regulates the production of cytokines. This study examined the role of RAMP1 signaling during lipopolysaccharide (LPS)-induced acute lung injury (ALI). LPS administration to wild-type (WT) mice depleted alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) and neutrophils. RAMP1-deficient (RAMP1) mice exhibited higher lung injury scores, cytokine levels, and cytokine-producing neutrophil infiltration. RAMP1-deficient AMs produced more cytokines in response to LPS than WT AMs. Adoptive transfer of RAMP1-deficient AMs to RAMP1 mice increased cytokine levels and neutrophil accumulation compared to the transfer of WT AMs. RAMP1 mice had reduced MDM recruitment and lower pro-inflammatory and reparative macrophage profiles. Cultured bone marrow (BM)-derived RAMP1-deficient macrophages stimulated with LPS showed decreased expression of pro-inflammatory and pro-repairing genes. CGRP administration to WT mice reduced cytokine production and neutrophil accumulation. These findings indicate that RAMP1 signaling mitigates LPS-induced ALI by inactivating AMs and promoting inflammatory and repair activities of MDMs. Targeting RAMP1 signaling presents a potential therapeutic approach for the treatment of ARDS.
急性呼吸窘迫综合征（ARDS）是一种危及生命的肺部损伤，可导致细胞因子过度分泌。受体活性修饰蛋白（RAMP）1 是降钙素基因相关肽（CGRP）受体的一个亚基，可调节细胞因子的产生。本研究探讨了 RAMP1 信号在脂多糖（LPS）诱导的急性肺损伤（ALI）中的作用。LPS 给药可耗尽野生型（WT）小鼠的肺泡巨噬细胞（AMs），并募集单核细胞来源的巨噬细胞（MDMs）和中性粒细胞。RAMP1 缺陷（RAMP1）小鼠的肺损伤评分、细胞因子水平和产生细胞因子的中性粒细胞浸润更高。与 WT AMs 相比，RAMP1 缺陷 AMs 对 LPS 的反应产生更多细胞因子。与 WT AMs 相比，将 RAMP1 缺陷 AMs 过继转移到 RAMP1 小鼠中会增加细胞因子水平和中性粒细胞积聚。RAMP1 小鼠的 MDM 募集减少，促炎和修复性巨噬细胞表型降低。用 LPS 刺激培养的骨髓（BM）衍生的 RAMP1 缺陷巨噬细胞显示促炎和促修复基因的表达下调。CGRP 给药可降低 WT 小鼠的细胞因子产生和中性粒细胞积聚。这些发现表明，RAMP1 信号通过失活 AMs 并促进 MDM 的炎症和修复活性来减轻 LPS 诱导的 ALI。靶向 RAMP1 信号可能为治疗 ARDS 提供一种潜在的治疗方法。
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