title: Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids.
abstract: Microglia cells are the primary mediators of the CNS immune defense system and crucial for the outcome of shaping inflammatory responses. They are highly dynamic, moving constantly, and become activated by neuronal signaling under pathological conditions. They fulfill a dual role by not only regulating local neuroinflammation but also conferring neuronal protection. Gonadal steroids are known to exert anti-inflammatory effects in the CNS. Recently, we have shown that the microglial-like cell line BV-2 is hypoxia-sensitive and regulated by gonadal steroids. The present study used primary rat cerebral cortex-derived microglia to analyze whether this cell type directly perceive and respond to acute hypoxia. Second, we investigated whether 17β-estradiol (E2) and progesterone (P) interfere with hypoxia-induced changes. Short-term hypoxia increased the expression of a subset of pro-inflammatory (TNFa, IL1b) and oxidative stress-related (Hif1a) genes. The induction of TNFa and IL1b was counteracted by P. Hypoxia shifted the primary microglia to the pro-inflammatory M1 phenotype. The administration of E2 and P favored the neuroprotective M2 phenotype. Our findings extend previous data obtained with BV-2 cells and show that the primary microglia directly perceive hypoxia which increase their inflammatory activity. Both steroid hormones directly and indirectly interact with the microglia cells by reducing the inflammatory scenario and stimulating neuroprotection.
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, 52074, Aachen, Germany.
authors.forename: Pardes
authors.initials: P
authors.lastname: Habib
authors.forename: Alexander
authors.initials: A
authors.lastname: Slowik
authors.forename: Adib
authors.initials: A
authors.lastname: Zendedel
authors.forename: Sonja
authors.initials: S
authors.lastname: Johann
authors.forename: Jon
authors.initials: J
authors.lastname: Dang
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010641:Phenotype; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D004958:Estradiol