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Microglial Inflammatory Responses to Systemic Immune Challenge are Attenuated over the Course of Chronic Intermittent Hypoxia Exposure
Author(s) -
Ouellette Jonathan N.,
Smith Stephanie M.C.,
Watters Jyoti J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.746.2
Subject(s) - microglia , tlr4 , inflammation , intermittent hypoxia , lipopolysaccharide , systemic inflammation , immune system , receptor , hypoxia (environmental) , immunology , in vivo , medicine , innate immune system , tumor necrosis factor alpha , endocrinology , chemistry , biology , microbiology and biotechnology , organic chemistry , oxygen , obstructive sleep apnea
Intermittent hypoxia (IH) is a hallmark of sleep disordered breathing that causes significant neuronal death, in part, via elevated levels of neuroinflammatory molecules. We previously identified microglia as one cellular source of these pro‐inflammatory molecules in the CNS within 1–2 weeks of IH exposure. However, microglial responses during IH to a concomitant inflammatory challenge are not yet known, an important consideration given that sleep disordered breathing and systemic inflammation are common co‐morbidities. Toll‐like receptor 4 (TLR4) is an innate immune receptor whose activation mediates inflammation in response to gram‐negative bacterial lipopolysaccharide (LPS) and endogenous molecules released from injured/dying cells prevalent in the CNS during IH. We found that TLR4 activation was necessary for microglial pro‐inflammatory responses to IH in vitro , and that TLR4 mRNA and activated cell surface protein levels increase and remain elevated in microglia for at least 28 days of IH in vivo , suggesting that microglia in the brains of IH‐exposed mice may be primed for greater responsiveness to subsequent inflammatory challenges. To test this hypothesis, we evaluated inflammatory gene expression in immunomagnetically‐isolated microglia from adult male C57Bl/6 mice that received 7–14 days of either normoxia (room air) or IH (60–90 second intervals of 6.5–10.5% O 2 for 8–12 hours) followed by intraperitoneal injection of LPS (1 mg/kg; 14 hours) or vehicle (HBSS). Surprisingly, we found that LPS‐stimulated microglial pro‐inflammatory gene expression (COX‐2, IL‐1β, TNFα and CCL3) was significantly attenuated in IH‐exposed mice, whereas microglial expression of anti‐inflammatory/trophic factors (IFNβ and BDNF) was increased by IH alone (and unaltered by LPS in either O 2 condition). Studies to investigate microglial responses to other forms of systemic inflammation during IH are ongoing. These data suggest that microglial responses are not exaggerated during IH, despite chronically elevated TLR4 levels. Further, they support the idea that microglia undergo a phenotypic transition during chronic exposure to IH that dampens their ability to respond to inflammatory stimuli, perhaps as an adaptive or compensatory response to protect the CNS against continued IH insult. Support or Funding Information Supported by R01 HL111598 and R01 NS085226