Simple SummaryBlocking 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.AbstractClinical 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.