A Toll-Like Receptor 9 Antagonist Improves Bladder Function and White Matter Sparing in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, cytidine-phosphateguanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the proinflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCIelicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due to alterations in the inflammatory milieu. These findings indicate that the TLR9 antagonist has beneficial effects not only in reducing sensory deficits, but also on bladder dysfunction and tissue preservation. Thus, modulation of innate immune receptor signaling in the spinal cord can impact the effects of SCI.

Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship

“…Such therapeutics may include immunomodulators of inflammation-associated pathways, e.g., estrogen, IL-33, IL-37, and adiponectin signaling pathways [ 151 – 154 ]. Small-molecule agonists or antagonists and blocking antibodies that specifically recognize and deactivate a variety of receptors involved in transduction of inflammatory signals—e.g., interleukin receptors, toll-like receptors, integrins, and estrogen receptors—are promising tools to mitigate complications after SCI [ 55 – 57 , 92 , 155 – 158 ]. Intracellular components of inflammatory machinery, including enzymes and transcription factors, may also serve as therapeutic targets to resolve inflammation in multiple organs following SCI [ 159 – 164 ].…”

“…SCI may impair supraspinal control of the bladder and result in neurogenic bladder, characterized by dysfunction in bladder storage and emptying [ 90 – 92 ]. Accordingly, SCI patients have an increased risk of developing urinary tract infections and renal damage, both of which can be life-threatening [ 93 – 96 ].…”

Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury

“…Studies in our laboratory have focused on TLR9. We have shown that a TLR9 antagonist, oligodeoxynucleotide 2088 (ODN 2088), alleviates functional deficits and improves histopathology in mice sustaining an SCI [28,29]. We also reported that TLR9 immunoreactivity and mRNA are found in astrocytes, in vitro [15] and in vivo [30].…”

A toll-like receptor 9 antagonist restores below-level glial glutamate transporter expression in the dorsal horn following spinal cord injury

“…In addition to their role in initiating innate immunity in response to infection, TLRs bind endogenous ligands known as danger associated molecular patterns (DAMPs) that are released from damaged or necrotic cells 23 – 25 . As a result, TLRs have been implicated as mediators of sterile inflammation associated with central nervous system (CNS) injury 20 , 21 , 26 . Thirteen TLRs have been identified in mice.…”