Fibrinogen signalling in human iPSC-derived microglia

Abstract

In Alzheimer’s disease (AD) and multiple sclerosis (MS), microglia are exposed to the blood protein fibrinogen (FG), and we showed previously the response of primary-cultured rat microglia to FG. Here, we show human iPSC-derived microglia (iPS-Mg) respond to FG, inducing secretion of a range of cytokines and chemokines and activation of stress pathways. An increased pro-caspase 4/5 (and active caspase-4/5) expression was independent of ER stress. Furthermore, unlike LPS/ATP which led to canonical NLRP3 inflammasome pathway activation including caspase 1 activity and IL-1β secretion, FG, with or without ATP did not activate the classical inflammasome pathway, indicating FG induced cytokine secretion in human iPS-Mg through non-canonical NFκB pathways. We also investigated how the late-onset AD (LOAD) TREM2 risk factor R47H may influence these responses. Soluble TREM2 was not shed with FG, in contrast to LPS stimulation, but the presence of FG reduced Aβ1−42 phagocytosis by iPS-Mg and enhanced oxidative phosphorylation but not glycolysis. Stress pathway proteome analyses indicated FG induced expression of many proteins in TREM2 common variant (Cv) iPS-Mg some of which more highly expressed in the R47H variant. These findings point to discrete activation pathways in iPS-Mg in response to FG and suggest targets for intervention where blood-brain barrier dysfunction may allow parenchymal FG accumulation.