Introduction: Sepsis remains a leading cause of death in critically ill patients, driven by a dysregulated host response to infection. Alpha-melanocyte-stimulating hormone (α-MSH), a neuropeptide derived from proopiomelanocortin (POMC) in the hypothalamus and pituitary, has potent anti-inflammatory properties. However, the physiological role of endogenous α-MSH in sepsis remains poorly defined. We hypothesized that hypothalamic α-MSH, but not pituitary-derived α-MSH, mitigates the inflammatory response to endotoxemia and that exogenous α-MSH improves survival in sepsis.
Methods: We used constitutive (αMSH-KO) and conditional (αMSH-fl/fl) α-MSH knockout mice. Male wild-type and αMSH-KO mice (8 weeks old) received intraperitoneal (i.p.) injections of saline or lipopolysaccharide (LPS, 0.1-8.0 mg/kg). For rescue, mice were implanted with subcutaneous osmotic pumps delivering continuous saline or α-MSH (5 µg/d). Core temperature was monitored via telemetry or rectal probe, and plasma cytokines were quantified by multiplex immunoassay. Pituitary-specific deletion of α-MSH was achieved by crossing αMSH-fl/fl mice with Tbx19-Cre mice, and validated by mass spectrometry.
Results: Following low-dose LPS (0.1 mg/kg), αMSH-KO mice exhibited greater hypothermia and elevated plasma IL-1β, IL-6, MIP-1α and MIP-1β compared to wild-type controls. In contrast, Tbx19-Cre::αMSH-fl/fl mice had cytokine profiles comparable to wild-type littermates, suggesting pituitary-derived α-MSH is dispensable in this context. After high-dose LPS (8 mg/kg), αMSH-KO mice had worse survival than WT (35% vs 79%, p = 0.003). Continuous α-MSH infusion significantly improved survival (p = 0.003) and thermoregulation in αMSH-KO mice after high-dose LPS, but did not suppress circulating cytokine levels.
Conclusions: Hypothalamic α-MSH is essential for regulating inflammation, temperature and survival after exposure to LPS. Pituitary-derived α-MSH is not required for these protective effects. Notably, exogenous α-MSH rescues αMSH-KO mice from mortality and hypothermia via mechanisms independent of cytokine suppression. These findings identify α-MSH as a critical regulator of the host response to LPS and position α-MSH as a novel therapeutic target in sepsis.
