Serine Proteases and Chemokines in Neurotrauma: New Targets for Immune Modulating Therapeutics in Spinal Cord Injury

Abstract

: Progressive neurological damage after brain or spinal cord trauma causes loss of motor function and treatment is very limited. Clotting and hemorrhage occur early after spinal cord (SCI) and traumatic brain injury (TBI), inducing aggressive immune cell activation and progressive neuronal damage. Thrombotic and thrombolytic proteases have direct effects on neurons and glia, both healing and also damaging, bidirectional immune cell interactions. Serine proteases in the thrombolytic cascade, tissue- and urokinase-type plasminogen activators (tPA and uPA), as well as the clotting factor thrombin have varied effects, increasing neuron and glial cell growth and migration (tPA), or conversely causing apoptosis (thrombin) and activating inflammatory cell responses. tPA and uPA activate plasmin and matrix metalloproteinases (MMPs) that break down connective tissue allowing immune cell invasion, promoting neurite outgrowth. Serine proteases also activate chemokines. Chemokines are small proteins that direct immune cell invasion, but also mediate neuron and glial cell communication. We are investigating a new class of therapeutics, virus-derived immune modulators; One that targets coagulation pathway serine proteases and a second that inhibits chemokines. We have demonstrated that local infusion of these biologics after SCI reduces inflammation providing early improved motor function. Serp-1 is a Myxomavirus-derived serine protease inhibitor, a serpin, that inhibits both thrombotic and thrombolytic proteases. M-T7 is a virus-derived chemokine modulator. Here we review the roles of thrombotic and thrombolytic serine proteases and chemoattractant proteins, chemokines, as potential therapeutic targets for SCI. We discuss virus-derived immune modulators as treatments to reduce progressive inflammation and ongoing nerve damage after SCI.

Development and validation of a differentiation-related signature based on single-cell RNA sequencing data of immune cells in spinal cord injury

“…The severe, destructive, and persistent inflammatory response after spinal cord injury can exacerbate local tissue damage and lead to the development of syringomyelia, characterized by the infiltration of phagocytic macrophages at the injury site. In recent years, there has been a growing emphasis on understanding the immune microenvironment after spinal cord injury, leading to the exploration of various immunotherapeutic approaches for spinal cord injury repair, demonstrating promising therapeutic prospects [ [24] , [25] , [26] ]. The efficacy of therapeutic interventions for spinal cord injury (SCI) often fall below expectations, primarily due to factors such as the diverse immune microenvironment following SCI, among others.…”

Molecular Mechanisms in the Vascular and Nervous Systems following Traumatic Spinal Cord Injury

“…Based on the amino acid sequence inserted between the first two CC amino acids in the sequence, there are four categories of chemokines: C, CC, CXC, and CX3C. CC chemokines are associated with the activation and migration of monocytes and lymphocytes, whereas CXC chemokines are often linked to the activation and migration of neutrophils and macrophages [ 73 ]. After SCI, the CC chemokine subtype CCL2 is protective by recruiting macrophages to the site of the injury and promoting the conversion of macrophages into an anti-inflammatory, neuroprotective M2 phenotype.…”

Delayed administration of nafamostat mesylate inhibits thrombin-mediated blood–spinal cord barrier breakdown during acute spinal cord injury in rats

“…Mosaic serine proteases have diversified effects on SCI. There is protective effect on increasing neuron and glial cell proliferation and migration by tissue-type plasminogen activator (tPA) [ 8 , 10 ], as well as damaging effect on apoptosis and activating inflammatory and immune response by thrombin [ 11 ]. Serine protease neuropsin and protease M/neuros expressed by oligodendrocyte upregulate after SCI, and promote demyelination [ 12 ].…”

“…Serine protease neuropsin and protease M/neuros expressed by oligodendrocyte upregulate after SCI, and promote demyelination [ 12 ]. Thrombin, a widely studied serine protease targeted by nafamostat, is a multifunctional enzyme that is restricted from the CNS under physiological conditions [ 11 ]. Recent research has shown that it has a crucial role in traumatic brain injury (TBI), SCI, neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and ischemic stroke [ 13 , 14 ].…”