The toll-like receptor 2 agonist Pam3CSK4 is neuroprotective after spinal cord injury

Stivers, Nicole S.; Pelisch, Nicolas; Orem, Ben C.; Williams, Joshua; Nally, Jacqueline M.; Stirling, David P.

doi:10.1016/j.expneurol.2017.04.012

Cited by 25 publications

(13 citation statements)

References 77 publications

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“… 59 In a mouse model of SCI, activation of TLR2 through a sterile agonist 1 h post-SCI led to a neuroprotective microglia/macrophage phenotype and genetic ablation of TLR2 led to enhanced axonal damage post-SCI. 60 , 61 TLR4 plays a positive role in myelination post-SCI, because it was required for acute oligodendrocyte genesis in naïve mice, whereas mice lacking TLR4 after thoracic contusion SCI had decreased myelin sparing and functional recovery. 62 Intraspinal injection of the TLR4 ligand, HMGB1, into the low thoracic region of mice resulted in activation of macrophages/microglia and elicited neuroinflammation, whereas exposure to extracellular HMGB1 reduced DRG neurite outgrowth in vitro .…”

Section: Discussionmentioning

confidence: 99%

Persons with Chronic Spinal Cord Injury Have Decreased Natural Killer Cell and Increased Toll-Like Receptor/Inflammatory Gene Expression

Herman

Stein

Gibbs

et al. 2018

Journal of Neurotrauma

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Infections are the leading cause of death for individuals with traumatic spinal cord injury (SCI). Along with increased infection rates, inflammation is often also observed in persons with chronic SCI. Together, immunological changes post-SCI are also poised to impede neurological recovery and mediate common medical consequences of SCI, including atherogenesis and neuropathic pain. The molecular mechanisms contributing to increased infection susceptibility and inflammation in persons living with SCI are poorly understood. Here, we used tools of functional genomics to perform a pilot study to compare whole-blood gene expression in individuals with chronic SCI (≥1 year from initial injury; N = 31) and uninjured individuals (N = 26). We identified 1815 differentially expressed genes in all SCI participants and 2226 differentially expressed genes in persons with SCI rostral to thoracic level 5, compared to uninjured participants. This included marked downregulation of natural killer cell genes and upregulation of the proinflammatory Toll-like receptor signaling pathway. These data provide novel mechanistic insights into the causes underlying the symptoms of immune dysfunction in individuals living with SCI.

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Section: Discussionmentioning

confidence: 99%

Persons with Chronic Spinal Cord Injury Have Decreased Natural Killer Cell and Increased Toll-Like Receptor/Inflammatory Gene Expression

Herman

Stein

Gibbs

et al. 2018

Journal of Neurotrauma

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“…To further explore mechanisms underlying RGC survival mediated by Arid1a deletion, we performed the proteinprotein interactions (PPIs) of differentially expressed genes. Strikingly, we observed some of the 30 genes with the highest degree shown in the circular layout were related to neuronal survival, such as Stat1, Tlr2 (Figure 3D; Stivers et al, 2017;Liu et al, 2019).…”

Section: Transcriptome Analysis Reveals Dynamic Gene Expression Induced By Knocking Out Arid1a In Adult Rgcsmentioning

confidence: 95%

Loss of Arid1a Promotes Neuronal Survival Following Optic Nerve Injury

Peng

Dai

et al. 2020

Front. Cell. Neurosci.

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Trauma or neurodegenerative diseases trigger the retrograde death of retinal ganglion cells (RGCs), causing an irreversible functional loss. AT-rich interaction domain 1A (ARID1A), a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, has been shown to play crucial roles in cell homeostasis and tissue regeneration. However, its function in adult RGC regeneration remains elusive. Here, we show that optic nerve injury induces dynamic changes of Arid1a expression. Importantly, deleting Arid1a in mice dramatically promotes RGC survival, but insignificantly impacts axon regeneration after optic nerve injury. Next, joint profiling of transcripts and accessible chromatin in mature RGCs reveals that Arid1a regulates several genes involved in apoptosis and JAK/STAT signaling pathway. Thus, our findings suggest modulation of Arid1a as a potential therapeutic strategy to promote RGC neuroprotection after damage.

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“…Once released from a cell, HMGB1 can activate innate immune receptors including TLR4, TLR2, and the receptor for advanced glycation end products (RAGE) (Hori et al, 1995; Kokkola et al, 2005; Park et al, 2006; Park et al, 2004; Yu et al, 2006). These receptors are expressed by macrophages and glia and are important in regulating inflammation, gliosis, and demyelination after SCI (Church et al, 2016; Church et al, 2017; Gensel et al, 2015; Kigerl et al, 2014; Kigerl et al, 2007; Stirling et al, 2014; Stivers et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation

Kigerl

Lai

Wallace

et al. 2018

Brain, Behavior, and Immunity

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Inflammation is a ubiquitous but poorly understood consequence of spinal cord injury (SCI). The mechanisms controlling this response are unclear but culminate in the sequential activation of resident and recruited immune cells. Collectively, these cells can exert divergent effects on cell survival and tissue repair. HMGB1 is a ubiquitously expressed DNA binding protein and also a potent inflammatory stimulus. Necrotic cells release HGMB1, but HMGB1 also is actively secreted by inflammatory macrophages. A goal of this study was to quantify spatio-temporal patterns of cellular HMGB1 expression in a controlled mouse model of experimental SCI then determine the effects of HMGB1 on post-SCI neuroinflammation and recovery of function. We documented SCI-induced changes in nuclear and cytoplasmic distribution of HMGB1 in various cell types after SCI. The data reveal a time-dependent increase in HMGB1 mRNA and protein with protein reaching maximal levels 24-72 h post-injury then declining toward baseline 14-28 days post-SCI. Although most cells expressed nuclear HMGB1, reduced nuclear labeling with increased cytoplasmic expression was found in a subset of CNS macrophages suggesting that those cells begin to secrete HMGB1 at the injury site. In vitro data indicate that extracelluar HMGB1 helps promote the development of macrophages with a neurotoxic phenotype. The ability of HMGB1 to elicit neurotoxic macrophage functions was confirmed in vivo; 72 h after injecting 500 ng of recombinant HMGB1 into intact spinal cord ventral horn, inflammatory CNS macrophages co-localized with focal areas of neuronal killing. However, attempts to confer neuroprotection after SCI by blocking HMGB1 with a neutralizing antibody were unsuccessful. Collectively, these data implicate HMGB1 as a novel regulator of post-SCI inflammation and suggest that inhibition of HMGB1 could be a novel therapeutic target after SCI. Future studies will need to identify better methods to deliver optimal concentrations of HMGB1 antagonists to the injured spinal cord.

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The toll-like receptor 2 agonist Pam3CSK4 is neuroprotective after spinal cord injury

Cited by 25 publications

References 77 publications

Persons with Chronic Spinal Cord Injury Have Decreased Natural Killer Cell and Increased Toll-Like Receptor/Inflammatory Gene Expression

Persons with Chronic Spinal Cord Injury Have Decreased Natural Killer Cell and Increased Toll-Like Receptor/Inflammatory Gene Expression

Loss of Arid1a Promotes Neuronal Survival Following Optic Nerve Injury

High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation

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