As neuronal activity drives acid loading in presynaptic terminals, we hypothesized that the same activity might drive acid efflux mechanisms to maintain pH cyto homeostasis. Collectively, our results indicate that astrocytic sANPEP-induced increase in Ang IV exacerbates neuroinflammation by interacting with microglial proinflammatory receptor AT1R, highlighting an important role of indirect crosstalk between astrocytes and microglia through the brain RAS in neuroinflammation.Neuronal activity can result in transient acidification of presynaptic terminals, and such shifts in cytosolic pH (pH cyto) probably influence mechanisms underlying forms of synaptic plasticity with a presynaptic locus. In a mouse neuroinflammation model, brain microglial activation and proinflammatory cytokine expression levels were increased by intracerebroventricular injection of sANPEP and attenuated by an enzymatic inhibitor and neutralizing antibody against sANPEP. Moreover, interleukin-1β release from human microglial cells was synergistically increased by cotreatment with sANPEP and its substrate, Ang III, suggesting the proinflammatory action of Ang IV generated by sANPEP.
The expression of AT1R was considerably upregulated in activated human microglial cells but not in human astrocytes. To elucidate the role of sANPEP and Ang IV in neuroinflammation, we first evaluated the expression of Ang IV receptors (ATRs) in human glial cells because Ang IV mediates biological effects through its receptors. We observed that the levels of soluble aminopeptidase N (sANPEP), a RAS component that converts angiotensin (Ang) III to Ang IV in a neuroinflammatory milieu, significantly increased in the astrocyte secretome. A total of 149 proteins were significantly upregulated in stimulated astrocytes, and a bioinformatics analysis of the astrocyte secretome revealed that the brain renin–angiotensin system (RAS) is an important mechanism of astrocyte communication. To understand how astrocytes communicate during neuroinflammation, we profiled the secretome of human astrocytes following stimulation with proinflammatory factors. Astrocytes are major supportive glia and immune modulators in the brain they are highly secretory in nature and interact with other cell types via their secreted proteomes.
0 kommentar(er)
