Prevention of the Severity of Post-ischemic Inflammation and Brain Damage by Simultaneous Knockdown of Toll-like Receptors 2 and 4

Koteswara Rao Nalamolu, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA.
Nathan J. Smith, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA.
Bharath Chelluboina, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA.
Jeffrey D. Klopfenstein, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA; Department of Neurosurgery, University of Illinois College of Medicine, Peoria, IL, USA; Comprehensive Stroke Center, Illinois Neurological Institute, OSF HealthCare System, Saint Francis Medical Center, Peoria, IL, USA.
David M. Pinson, Department of Pathology, University of Illinois College of Medicine, Peoria, IL, USA.
David Z. Wang, Department of Neurology, University of Illinois College of Medicine, Peoria, IL, USA; Comprehensive Stroke Center, Illinois Neurological Institute, OSF HealthCare System, Saint Francis Medical Center, Peoria, IL, USA.Follow
Raghu Vemuganti, Department of Neurological Surgery, School of Medicine and Public Health University of Wisconsin, Madison, WI, USA; William S. Middleton VA Hospital, Madison, WI, USA.
Krishna Kumar Veeravalli, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA; Department of Neurosurgery, University of Illinois College of Medicine, Peoria, IL, USA; Department of Neurology, University of Illinois College of Medicine, Peoria, IL, USA. Electronic address: krishnav@uic.edu.

Document Type

Article

Abstract

Toll-like receptor 2 (TLR2) and TLR4 belong to a family of highly conserved pattern recognition receptors and are well-known upstream sensors of signaling pathways of innate immunity. TLR2 and TLR4 upregulation is thought to be associated with poor outcome in stroke patients. We currently show that transient focal ischemia in adult rats induces TLR2 and TLR4 expression within hours and shRNA-mediated knockdown of TLR2 and TLR4 alone and in combination decreases the infarct size and swelling. We further show that TLR2 and TLR4 knockdown also prevented the induction of their downstream signaling molecules MyD88, IRAK1, and NFκB p65 as well as the pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This study thus shows that attenuation of the severity of TLR2- and TLR4-mediated post-stroke inflammation ameliorates ischemic brain damage.

Medical Subject Headings

Animals; Brain Edema (etiology, metabolism, prevention & control); Brain Ischemia (complications, metabolism, therapy); Disease Models, Animal; Escherichia coli; Gene Knockdown Techniques; Inflammation (etiology, metabolism, prevention & control); Interleukin-1 Receptor-Associated Kinases (metabolism); Interleukin-1beta (metabolism); Interleukin-6 (metabolism); Male; Myeloid Differentiation Factor 88 (metabolism); Neoplasm Proteins (metabolism); Neuroprotection (physiology); Nucleocytoplasmic Transport Proteins (metabolism); RNA, Messenger (metabolism); RNA, Small Interfering (administration & dosage); Random Allocation; Rats, Sprague-Dawley; Toll-Like Receptor 2 (genetics); Toll-Like Receptor 4 (genetics); Tumor Necrosis Factor-alpha (metabolism)

Publication Date

3-1-2018

Publication Title

Neuroscience

E-ISSN

1873-7544

Volume

373

First Page

82

Last Page

91

PubMed ID

29337240

Digital Object Identifier (DOI)

10.1016/j.neuroscience.2018.01.014

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