Inflammatory Mechanisms of Dysfunction after Polytraumatic SCI

About This Grant

PROJECT SUMMARY Spinal cord injury (SCI) produces a devastating syndrome that is characterized by motor and sensory dysfunction. In the human clinical population, SCI is often accompanied by concomitant injuries that vary from bone fracture, skin abrasion, and lacerations (polytraumatic SCI). These peripheral injuries likely contribute to spinal cord dysfunction, but their impact is largely unknown. The impact of peripheral injury on the spinal cord below the SCI may be overlooked. We have previously used several models of peripheral injury to demonstrate that polytraumatic SCI exacerbates neuroinflammation and maladaptive spinal plasticity, and can act to further undermine recovery of locomotor/sensory function. Interestingly, neuroinflammation contributes mechanistically to lumbar cord dysfunction below SCI. We have also demonstrated that peripheral nociceptive input increases and prolongs the inflammatory cytokine expression profile in the injured spinal cord. These findings suggest that polytrauma creates a vulnerability to neuroinflammation after SCI. The proposed R01 will explicitly test the hypotheses that 1) the precise immunomodulatory mechanism(s) by which peripheral injury alters spinal cord function after SCI, 2) the contribution of peripheral circulating immune cells, and 3) whether general anti-inflammatory or targeted block of peripheral immune cells reduce spinal cord neuroinflammation and improve recovery of behavioral function in polytraumatic SCI. We will test three models of peripheral injury (hindpaw capsaicin; spared nerve injury; tibial fracture) combined with contusive SCI, followed by a central anti-inflammatory (i.t. sTNFR1) or a systemic CCR2 antagonist (i.p. INCB3344) to assess the unique contributions of central neuroinflammatory vs. peripheral immune/inflammatory responses. Tibia fracture is hypothesized to cause more peripheral inflammation by mobilizing resident bone marrow-derived monocytes into circulation, while pure nociception via TRPV1 and nerve injury are hypothesized to cause central inflammation via direct tetanic afferent input into the CNS. Aim 1 will employ RNAseq with advanced gene network analyses and histopathology to demonstrate how early neuroinflammatory blockade alters the distinct pathways and injury processes engaged by different forms of polytraumatic SCI. In Aim 2 we will use single cell mass cytometry (CyTOF) to identify the unique profile of pro- inflammatory cell populations that respond to polytraumatic SCI and verified against anatomical markers of injury, to determine how these cell types (eg resident microglia vs peripheral macrophages) are affected by early block of neuroinflammation. Aim 3 will use a battery of behavioral and sensory assessments to test whether the early targeted anti-inflammatory therapy restores long-term function after polytraumatic SCI. Together these aims are designed to identify the distinct roles of peripheral and innate immune response and central neuroinflammation as drivers of persistent behavioral and sensory dysfunction in response to polytraumatic SCI, and to test the therapeutic efficacy of two anti-inflammatory precision-medicine approaches.