Abstract
Pericytes play a central role in regulating the structure and function of capillaries in the brain. However, molecular mechanisms that drive pericyte proliferation and differentiation are unclear. In our study, we immunostained NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-deficient and wild-type littermate mice and observed that NLRP3 deficiency reduced platelet-derived growth factor receptor β (PDGFRβ)-positive pericytes and collagen type IV immunoreactive vasculature in the brain. In Western blot analysis, PDGFRβ and CD13 proteins in isolated cerebral microvessels from the NLRP3-deficient mouse brain were decreased. We further treated cultured pericytes with NLRP3 inhibitor, MCC950, and demonstrated that NLRP3 inhibition attenuated cell proliferation but did not induce apoptosis. NLRP3 inhibition also decreased protein levels of PDGFRβ and CD13 in cultured pericytes. On the contrary, treatments with IL-1β, the major product of NLRP3-contained inflammasome, increased protein levels of PDGFRβ, and CD13 in cultured cells. The alteration of PDGFRβ and CD13 protein levels were correlated with the phosphorylation of AKT. Inhibition of AKT reduced both protein markers and abolished the effect of IL-1β activation in cultured pericytes. Thus, NLRP3 activation might be essential to maintain pericytes in the healthy brain through phosphorylating AKT. The potential adverse effects on the cerebral vascular pericytes should be considered in clinical therapies with NLRP3 inhibitors.
Highlights
Brain pericytes wrapping around endothelial cells regulate various functions in the brain, which include blood-brain barrier (BBB) permeability, angiogenesis, and capillary hemodynamic responses (Sweeney et al, 2016)
We observed widely distributed NLRP3-immune reactive cell bodies and processes, part of which were co-stained by platelet-derived growth factor receptor β (PDGFRβ)-specific antibodies (Figure 1A), which suggests that pericytes express NLRP3
We observed that the deletion of NLRP3 significantly reduced PDGFRβ and CD13 proteins in the cerebral blood vessels in a gene dose-dependent manner (Figures 1D,E; one-way ANOVA, p < 0.05; n ≥ 7 per group)
Summary
Brain pericytes wrapping around endothelial cells regulate various functions in the brain, which include blood-brain barrier (BBB) permeability, angiogenesis, and capillary hemodynamic responses (Sweeney et al, 2016). Pericytes express platelet-derived growth factor receptor β (PDGFRβ) and CD13. The binding of PDGFRβ with endothelial cells-released plateletderived growth factor (PDGF)-B is essential for pericyte proliferation and integration into the blood vessel (Lindahl et al, 1997). In the AD human brain, pericytes are lost in association with increased BBB permeability at a very early disease stage (Sengillo et al, 2013; Nation et al, 2019). In AD mouse models that overexpress Alzheimer’s precursor protein (APP) in neurons, the deletion of pericytes increases deposition of amyloid β peptide (Aβ) in both brain parenchyma and blood vessels, which potentially exaggerates cognitive deficits (Sagare et al, 2013). Molecular mechanisms that regulate pericyte survival and activation in the brain are largely unknown
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