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Rom S, Zuluaga-Ramirez V, Reichenbach NL, et al. PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier. J Neuroinflammation. 2016;13(1):254doi: 10.1186/s12974-016-0729-x.
Rom, S., Zuluaga-Ramirez, V., Reichenbach, N. L., Dykstra, H., Gajghate, S., Pacher, P., & Persidsky, Y. (2016). PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier. Journal of neuroinflammation, 13(1), 254. https://doi.org/10.1186/s12974-016-0729-x
Rom, Slava, et al. "PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier." Journal of neuroinflammation vol. 13,1 (2016): 254. doi: https://doi.org/10.1186/s12974-016-0729-x
Rom S, Zuluaga-Ramirez V, Reichenbach NL, Dykstra H, Gajghate S, Pacher P, Persidsky Y. PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier. J Neuroinflammation. 2016 Sep 27;13(1):254. doi: 10.1186/s12974-016-0729-x. PMID: 27677851; PMCID: PMC5039899.
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J Neuroinflammation. 2016 Sep 27;13(1):254. doi: 10.1186/s12974-016-0729-x.

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

Journal of neuroinflammation

Slava Rom, Viviana Zuluaga-Ramirez, Nancy L Reichenbach, Holly Dykstra, Sachin Gajghate, Pal Pacher, Yuri Persidsky

Affiliations

  1. Department of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, 19140, USA. [email protected].
  2. Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. [email protected].
  3. Department of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, 19140, USA.
  4. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, 20852, USA.
  5. Department of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, 19140, USA. [email protected].
  6. Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. [email protected].

PMID: 27677851 PMCID: PMC5039899 DOI: 10.1186/s12974-016-0729-x

Abstract

BACKGROUND: Blood-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.

METHODS: Cerebral 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

RESULTS: PARP 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.

CONCLUSIONS: These 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.

Keywords: Actin cytoskeleton; LFA-1; Leukocyte-endothelial interaction; PARP-1; VLA-4

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