NLRP3 maintains healthy pericytes in the brain

Quan, Wenqiang; Luo, Qinghua; Tang, Qiqiang; Furihata, Tomomi; Liu, Dong; Faßbender, Klaus; Liu, Yang

doi:10.21203/rs.2.18793/v1

Cited by 2 publications

(2 citation statements)

References 34 publications

(52 reference statements)

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“…We acknowledge support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and Saarland University within the funding programme Open Access Publishing. The older version of this manuscript has been released as a pre-print at Research Square (Quan et al, 2019 ).…”

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confidence: 99%

NLRP3 Is Involved in the Maintenance of Cerebral Pericytes

Quan

Luo

Tang

et al. 2020

Front. Cell. Neurosci.

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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 domainscontaining 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.

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NLRP3 Is Involved in the Maintenance of Cerebral Pericytes

Quan

Luo

Tang

et al. 2020

Front. Cell. Neurosci.

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“…To this end, we conducted the pabinafusp alfa uptake assays utilizing human immortalized astrocyte and pericytes model cells, HASTR/ci35 and HBPC/ci37 cells. These cell lines were selected because we and other researchers have shown that they retain many of their original characteristics (Furihata et al, 2016;Kitamura et al, 2018;Umehara et al, 2018;Quan et al, 2020;Das et al, 2022).…”

Section: Characterization Of Pabinafusp Alfa Uptake By Human Astrocyt...mentioning

confidence: 99%

Transferrin receptor-targeting property of pabinafusp alfa facilitates its uptake by various types of human brain-derived cells in vitro

et al. 2023

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Pabinafusp alfa, which is an anti-mucopolysaccharidosis II drug, consists of iduronate-2-sulfatase (IDS) genetically fused with an anti-transferrin receptor (TfR) antibody. While IDS is known to enter cells via mannose-6-phosphate receptor (M6PR)-mediated endocytosis, the anti-TfR antibody moiety of pabinafusp alfa is supposed to trigger the TfR-mediated transcytosis involved in its blood-brain barrier (BBB) penetration to deliver IDS into the brain, which thus makes it effective for treatment of brain symptoms of the disease. However, since these uptake processes remain unexamined in vitro, this study aims at elucidating how human brain cells manipulate these receptors to facilitate pabinafusp alfa uptake. The results of pabinafusp alfa uptake assays showed that the TfR played an primary role in its uptake by brain microvascular endothelial cells. The TfR contribution was also found in neuronal cells at levels comparable to M6PR. Interestingly, the predominant roles of TfR over M6PR in pabinafusp alfa uptake were also observed in astrocytes and pericytes. To summarize, our results support the TfR-targeting strategy of pabinafusp alfa for facilitating its BBB penetration while simultaneously identifying previously unnoticed TfR roles in its uptake into human neuronal and non-neuronal brain cells. These findings are certain to provide important insights into the mechanisms behind clinical actions of pabinafusp alfa.

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NLRP3 maintains healthy pericytes in the brain

Abstract: Background Pericytes regulate structure and function of cerebral capillaries. Growing evidence shows

Cited by 2 publications

References 34 publications

NLRP3 Is Involved in the Maintenance of Cerebral Pericytes

NLRP3 Is Involved in the Maintenance of Cerebral Pericytes

Transferrin receptor-targeting property of pabinafusp alfa facilitates its uptake by various types of human brain-derived cells in vitro

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