Selective Inhibition of Soluble Tumor Necrosis Factor Alters the Neuroinflammatory Response following Moderate Spinal Cord Injury in Mice

SIMPLE SUMMARY: Blocking detrimental neuroinflammation and boosting a pro-regenerative environment are promising new therapeutic approaches in spinal cord injury (SCI). Selective blocking of the soluble (sol) form of the cytokine tumor necrosis factor (TNF) while maintaining the membrane-bound form of TNF (tmTNF) has shown beneficial effects in pre-clinical models of SCI. In the present study, we investigated the effects of selective solTNF inhibition on the spatio-temporal inflammatory response after SCI in mice. We found that the blocking of solTNF alleviated the pro-inflammatory response, altered microglial responses, increased myelin preservation, and improved functional outcomes. Altogether, this demonstrates that selective inhibition of solTNF holds translational potential after SCI. ABSTRACT: Clinical and animal model studies have implicated inflammation and glial and peripheral immune cell responses in the pathophysiology of spinal cord injury (SCI). A key player in the inflammatory response after SCI is the pleiotropic cytokine tumor necrosis factor (TNF), which exists both in both a transmembrane (tmTNF) and a soluble (solTNF) form. In the present study, we extend our previous findings of a therapeutic effect of topically blocking solTNF signaling after SCI for three consecutive days on lesion size and functional outcome to study the effect on spatio-temporal changes in the inflammatory response after SCI in mice treated with the selective solTNF inhibitor XPro1595 and compared to saline-treated mice. We found that despite comparable TNF and TNF receptor levels between XPro1595- and saline-treated mice, XPro1595 transiently decreased pro-inflammatory interleukin (IL)-1β and IL-6 levels and increased pro-regenerative IL-10 levels in the acute phase after SCI. This was complemented by a decrease in the number of infiltrated leukocytes (macrophages and neutrophils) in the lesioned area of the spinal cord and an increase in the number of microglia in the peri-lesion area 14 days after SCI, followed by a decrease in microglial activation in the peri-lesion area 21 days after SCI. This translated into increased myelin preservation and improved functional outcomes in XPro1595-treated mice 35 days after SCI. Collectively, our data suggest that selective targeting of solTNF time-dependently modulates the neuroinflammatory response by favoring a pro-regenerative environment in the lesioned spinal cord, leading to improved functional outcomes.