Alpha-melanocyte-stimulating hormone contributes to an anti-inflammatory response to lipopolysaccharide

Objective: During infection, metabolism and immunity react dynamically to promote survival through mechanisms that remain unclear. Pro-opiomelanocortin (POMC) cleavage products are produced and released in the brain and in the pituitary gland. One POMC cleavage product, alpha-melanocyte-stimulating hormone (α-MSH), is known to regulate food intake and energy expenditure and has anti-inflammatory effects. However, it is not known whether α-MSH is required to regulate physiological anti-inflammatory responses. We recently developed a novel mouse model with a targeted mutation in Pomc (Pomc^tm1/tm1 mice) to block production of all α-MSH forms which are required to regulate metabolism. To test whether endogenous α-MSH is required to regulate immune responses, we compared acute bacterial lipopolysaccharide (LPS)-induced inflammation between Pomc^tm1/tm1 and wild-type Pomc^wt/wt mice. Methods: We challenged 10- to 14-week-old male Pomc^tm1/tm1 and Pomc^wt/wt mice with single i.p. injections of either saline or low-dose LPS (100 μg/kg) and monitored immune and metabolic responses. We used telemetry to measure core body temperature (T_b), ELISA to measure circulating cytokines, corticosterone and α-MSH, and metabolic chambers to measure body weight, food intake, activity, and respiration. We also developed a mass spectrometry method to measure three forms of α-MSH produced in the mouse hypothalamus and pituitary gland. Results: LPS induced an exaggerated immune response in Pomc^tm1/tm1 compared to Pomc^wt/wt mice. Both groups of mice were hypoactive and hypothermic following LPS administration, but Pomc^tm1/tm1 mice were significantly more hypothermic compared to control mice injected with LPS. Pomc^tm1/tm1 mice also had reduced oxygen consumption and impaired metabolic responses to LPS compared to controls. Pomc^tm1/tm1 mice had increased levels of key proinflammatory cytokines at 2 h and 4 h post LPS injection compared to Pomc^wt/wt mice. Lastly, Pomc^wt/wt mice injected with LPS compared to saline had increased total α-MSH in circulation 2 h post injection. Conclusions: Our data indicate endogenous α-MSH contributes to the inflammatory immune responses triggered by low-dose LPS administration and suggest that targeting the melanocortin system could be a potential therapeutic for the treatment of sepsis or inflammatory disease.