Temperature-Related Effects of Adenosine Triphosphate-Activated Microglia on Pro-Inflammatory Factors

Abstract

Lowering temperature rapidly reduced p38 activation and the subsequent p38-regulated production of pro-inflammatory cytokines and NO in ATP-activated microglia, suggesting that attenuation of early phase inflammatory responses via suppression of p38 in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Temperature elevation increased TNF-α and NO production in these cells. These temperature-dependent changes imply that monitoring of TNF-α and NO in the cerebrospinal fluid during the early phase might be useful as biomarkers for responses to therapeutic hypothermia and hyperthermia.

Original article Effects of hypothermia on ex vivo microglial production of pro- and anti-inflammatory cytokines and nitric oxide in hypoxic-ischemic brain-injured mice

“…In addition, an ex vivo culture of microglia isolated from CNS preserves the in vivo phenotype of microglia [18,51]. Importantly, as mentioned above, in terms of the temporal changes of neuroinflammatory responses, our present ex vivo findings, as well as our previous in vitro findings [33][34][35][36], appear to be similar to the in vivo findings for brain injury [9,11], as well as to those regarding IL-10 in vivo, which indicate that the levels in the brain show a peak during the first days (24-48 h) after brain injury [6,14,25]. Temporal similarity between the ex vivo and in vivo expressions of a signalling molecule in microglia has also been reported [12,51].…”

“…With the aim of elucidating the possible mechanisms underlying the neuroprotective effects of therapeutic hypothermia, we have previously shown that hypothermia reduces the production of earlyphase and late-phase inflammatory factors as well as that of late-phase anti-inflammatory factor in primary microglia in vitro [33][34][35][36]. We considered that an approach using microglia removed directly from injured brains may yield more clinically relevant information.…”

“…*p < 0.05 compared with 37°C. therapeutic hypothermia [33][34][35][36]. IL-10 has been considered to be neuroprotective because it reduces the production of pro-inflammatory cytokines [8,26].…”

“…A colorimetric assay with Griess reagent (Sigma-Aldrich) was performed, as described in our previous reports [33][34][35][36].…”

“…Previously, we and other groups have demonstrated a reduced production of tumour necrosis factor-alpha (TNF-α: another pro-inflammatory cytokine that is associated with neuronal injury [3,40]), IL-6, interferon-beta (IFN-β, which is known to be associated with neuronal cell death [15]), interleukin-10 (IL-10: an anti-inflammatory cytokine), and NO in hypothermic culture conditions [20,31,[33][34][35][36]42]. In particular, we proposed that these effects were temporally related to the reduction of early-phase and late-phase inflammatory factors as well as that of late-phase anti-inflammatory factor(s) [33][34][35][36].…”