Atsushi Yamashita: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Japan. ORCID
Yoshiya Ito: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Japan.
Mayuko Osada: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Japan.
Hiromi Matsuda: Department of Anesthesiology, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
Kanako Hosono: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Japan.
Kazutake Tsujikawa: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Hirotsugu Okamoto: Department of Anesthesiology, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
Hideki Amano: Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Japan. ORCID
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.
