Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced SIRS. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homiotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increased sympathetic activity, and may affect disease severity. This study was aimed at determining the impact of thermoregulatory responses upon reduced Ta exposition and the specific role of PI3Kγ in the pathogenesis of SAE. Experiments were performed in PI3Kγ wild-type, knockout, and kinase-dead mice, which were kept at neutral (30±0.5°C) or moderately lowered (26±0.5°C) Ta. Mice were exposed to LPS-induced SIRS and monitored for thermoregulatory response and bloodbrain barrier (BBB) integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. We found that a moderate reduction of Ta led to enhanced hypothermia of mice undergoing LPS-induced SIRS when compared to control mice accompanied by aggravated SIRS-induced SAE. PI3Kγ deficiency enhances BBB injury and upregulation of matrix metalloproteinases as well as an impairment of microglial phagocytic activity. This study reveals that enhanced adaptive thermoregulatory mechanisms in response to temperatures below the thermoneutral range of Ta and lead to exacerbated LPS-induced BBB injury and accompanied neuroinflammation. The signaling protein PI3Kγ was characterized as a critical mediator of key microglial cell functions involved in LPSinduced BBB injury and accompanied neuroinflammation. PI3Kγ serves a protective role in that it suppresses MMP release, maintains microglial motility and reinforces phagocytosis leading to improved brain tissue integrity.