Pneumonia constitutes a serious medical complication and major cause of death in patients after cerebral stroke. In a mouse model of cerebral ischemia (MCAO), we have recently demonstrated that stroke animals spontaneously develop severe bacterial pneumonia which is preceded by a stress-mediated suppression of cellular immune responses in primary and secondary lymphoid organs. However, little is known about the mechanisms leading to impaired pulmonary antimicrobial immune response after cerebral ischemia. In this study, we demonstrate a rapid up-regulation of the immunomodulatory neuropeptide alpha-melanocyte-stimulating hormone (MSH) in the lung within 24 h after cerebral ischemia. Systemic administration of the naturally occurring alpha-MSH receptor-1 (MC-1R) antagonist agouti immediately after MCAO significantly reduced pulmonary bacterial burden at 72 h. In contrast, administration of recombinant alpha-MSH further increased bacterial load in lungs of MCAO animals. In addition, cerebral ischemia resulted in a strong modulation of local pulmonary immunity with increased production of IL-10 by lung macrophages, reduced pulmonary lymphocyte counts, as well as decreased lymphocytic IFN-gamma but increased IL-4 production. However, alpha-MSH blockade by administration of agouti did not prevent changes in lung immune cell numbers or cytokine production suggesting that suppression of cellular immune responses is not the primary mechanism of alpha-MSH mediated inhibition of pulmonary antibacterial defenses. This study indicates an important role of alpha-MSH for the increased infectious susceptibility after cerebral ischemia and may provide new therapeutic strategies to prevent post-stroke infectious complications.