Impact of ambient temperature on inflammation-induced encephalopathy in endotoxemic mice—role of phosphoinositide 3-kinase gamma

Journal of Neuroinflammation

Reinhard Wetzker¹  Michael Brodhun²  Yingying Han³  Reinhard Bauer⁴  Trim Lajqi⁵  Bernadin Ndongson-Dongmo⁶  Guang-Ping Lang⁷  Martin G. Frasch⁸ 

[1] Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany;Department of Pathology, Helios-Klinikum Erfurt, Erfurt, Germany;Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany;Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Hans-Knöll-Straße 2, D-07745, Jena, Germany;Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Hans-Knöll-Straße 2, D-07745, Jena, Germany;Department of Neonatology, University Children’s Hospital, Heidelberg, Germany;Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Hans-Knöll-Straße 2, D-07745, Jena, Germany;Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway;Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Hans-Knöll-Straße 2, D-07745, Jena, Germany;Joint International Research Laboratory of Ethnomedicine and Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, 563006, Zunyi, China;University of Washington School of Medicine, Seattle, WA, USA;

关键词: Neuroinflammation;    Ambient temperature;    Microglia;    Phosphoinositide 3-kinase γ;    Blood–brain barrier;    Matrix metalloproteinases;    Phagocytosis;    Migration;   

DOI  :  10.1186/s12974-020-01954-7

来源: Springer

【 摘 要 】

BackgroundSepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3Kγ-dependent manner.MethodsExperiments were performed in wild-type, PI3Kγ knockout, and PI3Kγ kinase-dead mice, which were kept at neutral (30 ± 0.5 °C) or moderately lowered (26 ± 0.5 °C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10 μg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection)—evoked systemic inflammatory response (SIR) and monitored 24 h for thermoregulatory response and blood–brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm–Sidak test or t tests with Bonferroni’s correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn’s multiple comparisons test.ResultsWe show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3Kγ deficiency enhances blood–brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity.ConclusionsThermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood–brain barrier injury and neuroinflammation. PI3Kγ serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.

【 授权许可】

CC BY