Trained Immunity Characteristics Are Associated With Progressive Cerebral Small Vessel Disease
Background and Purpose Cerebral small vessel disease (cSVD) is the major vascular cause of cognitive decline and dementia. The pathogenesis of cSVD remains largely unknown, although several studies suggest a role for systemic inflammation. In certain pathophysiological situations, monocytes can reprogram toward a long term proinflammatory phenotype, which has been termed trained immunity. We hypothesize that trained immunity contributes to the progression of cSVD. Methods Individuals with mild to severe cSVD participated in the study. Severity of cSVD was determined by the white matter hyperintensities (WMH) volume (mL) on magnetic resonance imaging in 2006, 2015, and the progression between 2006 and 2015 &Dgr;WMH) Cytokine production was assessed after ex vivo stimulation of peripheral blood mononuclear cells and monocytes. Additionally, monocyte subsets were identified by flow cytometry. Results Fifty one subjects (70+ 6 years, 60% men, 5.1+ 6.4 mL &Dgr;WMH) were included. Circulating hsIL (high sensitivity interleukin) 6 correlated with cSVD (P=0.005, rs=0.40) Cytokine production capacity by monocytes was associated with cSVD progression. Basal IL 8 and IL 17 production (P=0.08, rs=0.25; P=0.03, rs=0.30) and IL 6 production after Pam3Cys stimulation in monocytes was associated with cSVD (n=35: P=0.008, rs=0.44) Conversely, interferon (IFN) &ggr; production in Candida albicans stimulated peripheral blood mononuclear cells was negatively correlated with cSVD (P=0.009, rs= 0.36) Flow cytometry revealed a correlation of the intermediate monocyte subset with cSVD (P=0.01, rs=0.36) Conclusions Severity and progression of cSVD are not only correlated with systemic inflammation (hsIL 6) but also with trained immunity characteristics of circulating monocytes, in terms of an altered cytokine production capacity and a shift toward the proinflammatory intermediate monocyte subset.
Stroke