(764.2) Neonatal and adult heterotypic inflammation sex-dependently prime adult microglia in respiratory control regions without impairing adult breathing

Poster Board Number: E557

Robyn Naidoo (University of Oregon), Sarah Beyeler (University of Oregon), Adrianne Huxtable (University of Oregon)

Adults often encounter diverse inflammatory stimuli, yet only some adults are prone to breathing deficits after adult inflammation. The determinants of adult susceptibility to breathing deficits during inflammation is understudied and likely involves microglia, the resident immune cells of the central nervous system. In non-respiratory control regions, neonatal inflammation primes adult microglia for exaggerated inflammatory responses to otherwise harmless inflammatory stimuli, such as adult subthreshold heterotypic inflammation (differing neonatal and adult inflammatory stimuli). Since male and female microglia have sexually dimorphic developmental trajectories, we hypothesized that neonatal inflammation would sex-dependently prime adult microglia in respiratory control regions to subthreshold heterotypic inflammation, contributing to impaired adult breathing. Using flow cytometry to assess microglia number (%CD11bhighCD45low / homogenates) and priming, adult male medullary microglia after neonatal inflammation (LPS 1mg/kg, i.p.) and adult subthreshold heterotypic inflammation (polyIC 478ug/kg, i.p.) were primed (neonatal LPS + adult polyIC: 25±7% microglia n=9; neonatal LPS + adult saline: 18±2% microglia, n=9; neonatal saline + adult saline: 10±2% microglia, n=9, plt;0.05; neonatal saline + adult polyIC: 11±2% microglia, n=8, plt;0.0001). In females, neonatal inflammation increased, but did not prime, medullary microglia to adult heterotypic inflammation (neonatal LPS + adult polyIC: 17±3% microglia, n=6; neonatal saline + adult saline: 11±1% microglia, n=6; neonatal saline + adult polyIC: 11±2% microglia, n=6, plt;0.005; neonatal LPS + saline: 14±2% microglia, n=8, pgt;0.9). To test whether these primed microglia in respiratory control regions contribute to adult breathing deficits, breathing was assessed using plethysmography in adults after neonatal and adult heterotypic inflammation. Contrary to our hypothesis, neonatal and adult heterotypic inflammation did not impair adult eupneic breathing, the hypercapnic ventilatory response, or the hypoxic ventilatory response in adult males (pgt;0.9) or females (pgt;0.9). Therefore, adults after neonatal and adult heterotypic inflammation are able maintain breathing in response to low levels of inflammation despite primed medullary microglia. Primed microglia, however, are prone to augmented inflammatory responses and may induce significant deficits to breathing when faced with more severe inflammatory challenges.

Supported by NIH HL141249 (AGH)