Neurotensin and Corticotropin‐releasing Hormone Synergistically Activate Human Microglia through Mammalian Target of Rapamycin Complex 1 (mTORC1)

Despite the rise in diagnoses of Autism Spectrum Disorder (ASD), its pathogenesis and treatment remain unknown. Mounting evidence supports the involvement of neuroinflammation and immune dysfunction. ASD has been associated with elevated serum levels of neurotensin (NT) and corticotropin‐releasing hormone (CRH) secreted under stress. Microglia, the resident brain immune cells, are critical gatekeepers of neuronal function and show aberrant growth in ASD brains. Mutations in proteins that regulate signaling through the mammalian target of rapamycin complex 1 (mTORC1), which regulates immune cell proliferation and mediator production, are seen in about 1‐5% of ASD. Here, we hypothesized that NT and CRH stimulate human microglia through activation of mTORC1 leading to proinflammatory mediator release. Our results show that microglia express the NT receptor‐3, which significantly increases following NT stimulation. NT and CRH, together, induce a 20‐fold higher gene expression of CRH receptor‐1 in microglia than either trigger alone. We also show increased expression and secretion of proinflammatory interleukin (IL)‐1beta from microglia after NT and CRH co‐stimulation. In response to either NT or CRH, microglia secrete IL‐6, CXCL8 and CCL2. Our results implicate the involvement of mTORC1 activation in microglia after stimulation with NT and CRH. Our findings will identify novel molecular targets for inhibition of hyperactive immune cells that show potential as ASD treatment.