RAMP1 signaling attenuates acute lung injury by inhibiting cytokine production and neutrophil recruitment

Neuroimmune interactions have emerged as critical regulators of inflammation. Neuropeptide calcitonin gene-related peptide (CGRP) regulates cytokine production in immune cells through signaling for CGRP receptor, receptor activity-modifying protein 1 (RAMP1). Here, we examined the role of RAMP1 signaling in LPS-induced lung injury. Acute lung injury was induced by intratracheal injection of LPS in wild-type mice (WT) and RAMP1 knockout mice (RAMP1 KO). Compared with WT, RAMP1 KO exhibited decreases in survival rate and increases in lung injury score, and total protein concentrations and pro-inflammatory mediators including IL-6 and CXCL2 in BALF at 72 h after LPS administration. In WT, CGRP and RAMP1 levels in the lung were increased after LPS administration, and RAMP1 was expressed in alveolar macrophages. After LPS administration, the numbers of alveolar macrophages in both types of mice were diminished, and reached nadir at 6h, and restored to half levels of pre-values in WT thereafter, but remained low in RAMP1 KO until up to 72 h. By contrast, the numbers of neutrophils were increasing with time after LPS administration in two genotypes, and those in RAMP1 KO were larger than WT at 72 h. These results suggested that RAMP1 signaling attenuated LPS-induced acute lung injury by inhibiting cytokine production, neutrophil accumulation, and pulmonary vascular permeability.