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

Abstract

Background Sepsis-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. Methods Experiments 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. Results We 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. Conclusions Thermoregulatory 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.

The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

“…The activation of cAMP/CREB signaling caused by missing PI3Kγ’s scaffold function and hence loss of phosphodiesterase (PDE) activation [ 39 , 56 ] may be responsible for distinct ETC uncoupling. Our immunometabolic data substantiate previous findings that loss of PI3Kγ’s scaffold function is causally related to proinflammatory sequels in different disease models including septic encephalopathy and its hypothermic aggravation [ 35 , 57 ], focal brain ischemia [ 36 ] and inflammation-induced myocardial depression in septic shock [ 38 ]. However, a molecular link between increased intracellular cAMP levels as well as a related signaling and mitochondrial disturbance with ETC uncoupling remains unknown and cannot be deduced from the present data.…”

Dehydrozaluzanin C- derivative protects septic mice by alleviating over-activated inflammatory response and promoting the phagocytosis of macrophages

“…All of TNF-α, interleukin, and interferonγcan induce hypothermia via regulating thermotaxic center of the brain (40,41). During infection, the activity of animals is reduced, which can also lead to the appearance of hypothermia (42) The load of pathogens is usually related to the severity of infectious diseases.…”

Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury

“…for induction of immunological preconditioning ( 31 ), or physiological saline (NaCl) as a single intraperitoneal injection. Clinical status was assessed 48h, 24h and immediately before unilateral tMCAO according to ( 32 , 33 ). Specifically, clinical status was assessed using a clinical severity score by scoring the status of spontaneous activity (Grade 1, No signs of illness, active, strong; Grade 2, Low-grad of illness, less active with occasional interruptions in activity; Grade 3, Mid-grade of illness, slow, sleepy, moves with difficulty; Grade 4, High-grade of illness, lethargic, motionless, no movement), reaction to exogenous stimuli (Grade 1, curious, quick movements; Grade 2, educed alertness, but adequate response; Grade 3, limited and delayed; Grade 4, none) and posture (Grade 1, normal; Grade 2, slightly hunched; Grade 3, hunched; Grade 4, severely hunched).…”