Estradiol, synthesized by reactive glia, is a potent anti-inflammatory in the injured vertebrate brain

Neuroinflammation following traumatic brain injury (TBI) may have detrimental and beneficial effects that likely differ between the acute and chronic periods post-trauma. In birds and mammals, traumatic brain injury increases the expression of cytokines in microglia and aromatase (estrogen synthase) in astroglia. In the songbird, TBI-induced synthesis of estrogens by glial aromatization is neuroprotective as aromatase inhibition and replacement with estradiol (E2) exacerbates and mitigates the extent of damage and apoptosis, respectively. The effect of glial estrogens on inflammation, however, remains unstudied. We hypothesized that induced astrocytic aromatization may affect neuroinflammation following TBI, via the synthesis of neural E2 around the site of damage. In three separate experiments on adult zebra finches (Taeniopygia guttata) of both sexes we tested the influence of (a) mechanical TBI, (b) inhibition of induced aromatase expression, and (c) inhibition of induced aromatase with central E2 replacement, on the expression of the pro-inflammatory cytokines TNFa, IL-1b and IL-6, and aromatase. At 2-hour post-injury, in both sexes, TBI increased, and tended to elevate, TNFa and IL-1b; respectively. At 24-hour post-injury, also in both sexes, cytokines appeared to have returned to baseline, but aromatase is robustly elevated in the lobe that sustained TBI. Pharmacological inhibition of induced aromatization resulted in persistent neuroinflammation, as administration of fadrozole increased IL-1b; in females and TNFa; in males 24 hour following TBI. This prolonged neuroinflammation following aromatase inhibition appears to be due to a failure to synthesize E2 locally, since E2 replacement lowered TNFa and IL-1b relative to fadrozole alone. IL-6 was not affected by TBI, aromatase inhibition or E2 replacement in either sex. These data suggest that astrocytic E2 synthesis following TBI is a potent and inducible anti-inflammatory signal, with specific modulation of discrete cytokine signaling. Induced neural provision of E2 following damage and compromise of central pathways may protect the brain from the deleterious effects of prolonged neuroinflammation.