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Tlr4 Deletion Modulates Cytokine and Extracellular Matrix Expression in Chronic Spinal Cord Injury, Leading to
Fari Ryan1, Isaac Francos-Quijorna2, Gerard Hernández-Mir3
1Centre for Research in Neuroscience and BRaIN Program, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.
Abstract:
Toll-like receptors (TLRs) play an important role in the innate immune response after CNS injury. Although TLR4 is one of the best characterized, its role in chronic stages after spinal cord injury (SCI) is not well understood. We examined the role of TLR4 signaling in injury-induced responses at 1 d, 7 d, and 8 weeks after spinal cord contusion injury in adult female TLR4 null and wild-type mice. Analyses include secondary damage, a range of transcriptome and protein analyses of inflammatory, cell death, and extracellular matrix (ECM) molecules, as well as immune cell infiltration and changes in axonal sprouting and locomotor recovery. Lack of TLR4 signaling results in reduced neuronal and myelin loss, reduced activation of NFκB, and decreased expression of inflammatory cytokines and necroptotic cell death pathway at a late time point (8 weeks) after injury. TLR4 null mice also showed reduction of scar-related ECM molecules at 8 weeks after SCI, accompanied by increase in ECM molecules associated with perineuronal nets, increased sprouting of serotonergic fibers, and improved locomotor recovery. These findings reveal novel effects of TLR4 signaling in chronic SCI. We show that TLR4 influences inflammation, cell death, and ECM deposition at late-stage post-injury when secondary injury processes are normally considered to be over. This highlights the potential for late-stage targeting of TLR4 as a potential therapy for chronic SCI.
Insights
Toll-like receptor 4 (TLR4) signaling exacerbates chronic spinal cord injury (SCI) by promoting inflammation and cell death. Blocking TLR4 in mice improved recovery and reduced damage, suggesting late-stage TLR4 inhibition as a potential SCI therapy.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Toll-like receptors (TLRs) are crucial for innate immunity following central nervous system (CNS) injury.
- The specific role of Toll-like receptor 4 (TLR4) in the chronic phase of spinal cord injury (SCI) remains largely unknown.
Purpose of the Study:
- To investigate the function of TLR4 signaling in chronic SCI.
- To evaluate the impact of TLR4 deficiency on secondary damage, inflammation, cell death, extracellular matrix (ECM) remodeling, and functional recovery after SCI.
Main Methods:
- Spinal cord contusion injury was induced in adult female TLR4 null and wild-type mice.
- Analyses included secondary damage assessment, transcriptome and protein profiling of inflammatory and cell death markers, ECM molecule evaluation, immune cell infiltration assessment, and locomotor recovery testing at 1 day, 7 days, and 8 weeks post-injury.
Main Results:
- Lack of TLR4 signaling led to reduced neuronal and myelin loss, decreased NFκB activation, and lower expression of inflammatory cytokines and necroptotic cell death markers at 8 weeks post-injury.
- TLR4 null mice exhibited reduced deposition of scar-related ECM molecules and increased ECM associated with perineuronal nets.
- Absence of TLR4 signaling promoted serotonergic fiber sprouting and enhanced locomotor recovery in chronic SCI models.
Conclusions:
- TLR4 signaling plays a significant role in chronic SCI, influencing late-stage inflammation, cell death, and ECM deposition.
- Targeting TLR4 during the chronic phase of SCI may offer a novel therapeutic strategy for improving functional recovery.
