PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier

Abstract

BackgroundBlood-brain barrier (BBB) dysfunction/disruption followed by leukocyte infiltration into the brain causes neuroinflammation and contributes to morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. The identification of pathways that decreases the inflammatory potential of leukocytes would prevent such injury. Poly(ADP-ribose) polymerase 1 (PARP) controls various genes via its interaction with myriad transcription factors. Selective PARP inhibitors have appeared lately as potent anti-inflammatory tools. Their effects are outside the recognized PARP functions in DNA repair and transcriptional regulation. In this study, we explored the idea that selective inhibition of PARP in leukocytes would diminish their engagement of the brain endothelium.MethodsCerebral vascular changes and leukocyte-endothelium interactions were surveyed by intravital videomicroscopy utilizing a novel in vivo model of localized aseptic meningitis when TNFα was introduced intracerebrally in wild-type (PARP+/+) and PARP-deficient (PARP−/−) mice. The effects of selective PARP inhibition on primary human monocytes ability to adhere to or migrate across the BBB were also tested in vitro, employing primary human brain microvascular endothelial cells (BMVEC) as an in vitro model of the BBB.ResultsPARP suppression in monocytes diminished their adhesion to and migration across BBB in vitro models and prevented barrier injury. In monocytes, PARP inactivation decreased conformational activation of integrins that plays a key role in their tissue infiltration. Such changes were mediated by suppression of activation of small Rho GTPases and cytoskeletal rearrangements in monocytes. In vitro observations were confirmed in vivo showing diminished leukocyte-endothelial interaction after selective PARP suppression in leukocytes accompanied by BBB protection. PARP knockout animals demonstrated a substantial diminution of inflammatory responses in brain microvasculature and a decrease in BBB permeability.ConclusionsThese results suggest PARP inhibition in leukocytes as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation-induced leukocyte engagement.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0729-x) contains supplementary material, which is available to authorized users.

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…The effectiveness of clinically relevant inhibitors in many in vitro and in vivo models of inflammatory diseases has confirmed and further corroborated the hypothesis of beneficial effects of PARP inhibition therapy in humans. Studies include results relevant to stroke, neurodegeneration, neuroinflammation and blood brain barrier function [148,149], sepsis [150], liver diseases [151,152], and asthma [112]. Protection of human neuronal cells by in vitro oxidative stress or NMDA was shown with rucaparib, veliparib, talazoparib, and olaparib [153].…”

Cathepsin B inhibition ameliorates leukocyte‐endothelial adhesion in the BTBR mouse model of autism

“…BTBR mice partially recapitulate this phenotype and have abnormal immune responses, such as microglia activation and increased cytokine secretion . Adhesive interactions between endothelial cells and leukocytes are key cellular mediators for inflammation under pathological conditions . We recorded here for the first time the dynamic pathogenesis of leukocyte‐endothelial cell adhesion in ASD animal models, suggesting the systemic inflammation and activation of the local vasculature in BTBR mice.…”

“…[44][45][46][47] Adhesive interactions between endothelial cells and leukocytes are key cellular mediators for inflammation under pathological conditions. [48][49][50] We recorded here for the first time the dynamic pathogenesis of leukocyte-endothelial cell adhesion in ASD animal models, suggesting the systemic inflammation and activation of the local vasculature in BTBR mice. We determined that CD11b in neutrophils and ICAM-1 in endothelial cells were significantly higher in autistic mice, providing further support to previous reports that adhesion molecules may be essential in the pathophysiology of ASD, possibly by causing abnormalities in the immune system.…”

Poly(ADP-ribose) polymerase inhibitor olaparib hampers placental growth factor-driven activation of myelomonocytic cells

“…In this regard, PARP inhibition exerts protective effects blocking the pro-inflammatory activity of PARP-1. Indeed, treatment with PARP inhibitors (PARPi) of macrophages diminished the production of inflammatory mediators (16) and decreased monocytes adhesion and migration across the blood-brain barrier (BBB) in in vitro models by reducing the activation of specific integrins (17).…”