Deep hypothermia therapy attenuates LPS-induced microglia neuroinflammation via the STAT3 pathway

Neuroscience. 2017 Sep 1;358:201-210. doi: 10.1016/j.neuroscience.2017.06.055. Epub 2017 Jul 5.

Abstract

Deep hypothermia therapy (HT) is a standard method for neuroprotection during complex pediatric cardiac surgery involving extracorporeal circulation and deep hypothermic cardiac arrest. The procedure, however, can provoke systemic inflammatory response syndrome (SIRS), one of the most severe side effects associated with pediatric cardiac surgery. To date, the cellular inflammatory mechanisms induced by deep HT remain to be elucidated. Therefore, we investigated the effects of deep HT (17°C) and rewarming on the inflammatory response in lipopolysaccharide (LPS) stimulated BV-2 murine microglia. Additionally, we also investigated the application of Stattic, a signal transducer and activator of transcription 3 (STAT3) activation inhibitor, as an alternative to physical cooling to attenuate the LPS-induced inflammatory response. Deep HT had no cytotoxic effect but attenuated microglia migration. IκBα degradation was delayed by deep HT resulting in the attenuation of pNF-κB p65 migration into the nucleus and significant decreases in pro-inflammatory IL-6, TNF-α, and MCP-1 expressions and secretions, as well as decreased anti-inflammatory IL-10 and SOCS3 expressions. Additionally, pStat3 was significantly down regulated under deep hypothermic conditions, also corresponding with the significant reduction in IL-6 and TNF-α expressions. Similar to the effects of HT, the application of Stattic under normothermic conditions resulted in significantly reduced IL-6 and TNF-α expressions. Moreover, attenuation of the inflammatory response resulted in decreased apoptosis in a direct co-culture of microglia and neurons. HT reduces the inflammatory response in LPS-stimulated BV-2 microglial cells, alluding to a possible mechanism of therapeutic hypothermia-induced neuroprotection. In the future, attenuating the phospho-STAT3 pathway may lead to the development of a neuroprotectant with greater clinical efficacy.

Keywords: STAT3; hypothermia therapy; inflammation; microglia; neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5 / metabolism
  • Cell Line, Transformed
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Coculture Techniques
  • Cyclic S-Oxides / pharmacology
  • Dose-Response Relationship, Drug
  • Hypothermia, Induced / methods*
  • Interleukin-10 / metabolism
  • Lipopolysaccharides / toxicity*
  • Mice
  • Microglia / drug effects*
  • NF-kappa B / metabolism
  • Neurons / drug effects*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphorylation / drug effects
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Time Factors

Substances

  • Annexin A5
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Cyclic S-Oxides
  • Lipopolysaccharides
  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • stattic
  • Interleukin-10
  • Nitric Oxide
  • Nitric Oxide Synthase Type II