Neuropeptides stimulate pro-inflammatory mediator secretion from human microglia through mammalian target of rapamycin signaling, which is inhibited by the flavonoids luteolin and tetramethoxyluteolin (IRM9P.457)

Abstract

Abstract Despite the rise in diagnosis of Autism Spectrum Disorders (ASD, 1:68 children), the pathogenesis and treatment remain unknown. Mounting evidence supports the involvement of brain inflammation and immune dysfunction. Microglia, the brain-resident immune cells are critical gatekeepers of neuronal function show aberrant growth and activation in ASD brains. Some ASD patients also have elevated serum levels of neurotensin (NT) and corticotropin-releasing hormone (CRH), which are stress-related neuropeptides. Moreover, 1-5% of ASD cases have mutations in proteins that inhibit signaling through the mammalian target of rapamycin complex 1 (mTORC1), which regulates immune cell proliferation and mediator production. We hypothesized that NT and CRH act synergistically to stimulate human microglia through activation of mTORC1 leading to pro-inflammatory mediator release. We show that unstimulated human microglia express the NT receptor-3, but not the CRH receptor-1 (CRHR-1). Stimulation with NT and CRH significantly increases the gene expression of CRHR-1, as well as expression and secretion of the pro-inflammatory interleukin IL-1beta, CXCL8, CCL2, and GM-CSF. Pretreatment with mTORC1 inhibitors and the natural flavonoids luteolin and tetramethoxyluteolin, significantly decreases mediator secretion. Our results implicate the involvement of mTORC1 signaling for microglia activation, which is inhibited by novel flavonoids that could be developed into effective ASD treatments.