Deficiency of alpha-calcitonin gene-related peptide induces inflammatory responses and lethality in sepsis

Abstract

In the present study, we examined the role of alpha-calcitonin gene-related peptide (αCGRP) on expression of neuropeptides in the brain, inflammatory responses, and survival rate in septic shock condition. We examined expression of neuropeptides such as αCGRP, proopiomelanocortin (POMC), corticotrophin releasing hormone (CRH), and proenkephalin (ProENK) in the hippocampus and hypothalamus in C57BL/6 (WT) or αCGRP−/− (KO) mice subjected to sepsis. Cecal ligation and puncture (CLP) or lipopolysaccharide/D-galactosamine (LPS/D-GalN) treatment showed significant increases of hippocampal and hypothalamic αCGRP, POMC, CRH, and ProENK mRNA levels in WT mice, but not ProENK mRNA in the hypothalamus at 6h after on-set of sepsis. However, enhanced mRNA levels of POMC, CRH, and ProENK genes were not increased in the hippocampus and hypothalamus of CLP-subjected KO mice at 6h following sepsis. KO mice treated with LPS/D-GalN displayed a significant enhancement of plasma corticosterone, aspartate aminotransferase, and alanine aminotransferase levels compared to LPS/D-GalN treated WT mice at 12h after induction of sepsis. In addition, plasma levels of pro-inflammatory cytokines, such as IL-1β and TNF-α, were also further increased in KO mice compared to WT mice at 24h after CLP or LPS/D-GalN treatment. Interestingly, mRNA expressions of IL-6 and IL-10, anti-inflammatory cytokines, were synergistically enhanced in liver and lymph node of KO mice compared to WT mice at 6h after CLP. However, plasma level of IL-10 but not IL-6 was significantly decreased in KO mice compared to WT mice at 24h after CLP or LPS/D-GalN challenge. The survival rate of KO mice was significantly reduced compared to WT mice following mild (1 punch) and moderate (2 punch) CLP and LPS/D-GalN administration. Taken together, our findings suggest that the activation of αCGRP may induce other neuropeptides associated with immunomodulation at CNS level and modulate immune responses as enhancing anti-inflammatory cytokines and reducing pro-inflammatory cytokines during the sepsis.