Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6

Abstract

An important barrier for axon regeneration and recovery after traumatic spinal cord injury (SCI) is attributed to the scar that is formed at the lesion site. Here, we investigated the effect of mouse mast cell protease (mMCP) 6, a mast cell (MC)-specific tryptase, on scarring and functional recovery after a spinal cord hemisection injury. Functional recovery was significantly impaired in both MC-deficient and mMCP6-knockout (mMCP6 2/2 ) mice after SCI compared with wild-type control mice. This decrease in locomotor performance was associated with an increased lesion size and excessive scarring at the injury site. Axon growth-inhibitory chondroitin sulfate proteoglycans and the extracellular matrix components fibronectin, laminin, and collagen IV were significantly up-regulated in MC-deficient and mMCP6 2/2 mice, with an increase in scar volume between 23 and 32%. A degradation assay revealed that mMCP6 directly cleaves fibronectin and collagen IV in vitro. In addition, gene expression levels of the scar components fibronectin, aggrecan, and collagen IV were increased up to 6.8-fold in mMCP62/2 mice in the subacute phase after injury. These data indicate that endogenous mMCP6 has scarsuppressing properties after SCI via indirect cleavage of axon growth-inhibitory scar components and alteration of the gene expression profile of these factors.-Vangansewinkel, T., Geurts, N., Quanten, K., Nelissen, S., Lemmens, S., Geboes, L., Dooley, D., Vidal, P. M., Pejler, G., Hendrix, S. Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6.

Cell-Based Delivery of Interleukin-13 Directs Alternative Activation of Macrophages Resulting in Improved Functional Outcome after Spinal Cord Injury

“…A T-cut spinal cord hemisection injury was performed as previously described (Boato et al., 2010, Dooley et al., 2016, Geurts et al., 2015, Nelissen et al., 2013, Vangansewinkel et al., 2016, Vidal et al., 2013). See Supplemental Experimental Procedures for further details.…”

“…Spinal cord cryosections (10 μm) were obtained from animals transcardially perfused 4 weeks post injury with Ringer solution containing heparin, followed by 4% paraformaldehyde in 0.1 M PBS, and immunofluorescence analysis was performed as previously described (Boato et al., 2010, Dooley et al., 2016, Geurts et al., 2015, Nelissen et al., 2013, Vangansewinkel et al., 2016). See Supplemental Experimental Procedures for further details.…”

“…For measurement of lesion size and demyelinated area, five to seven sections per animal (WT BALB/c: n = 6–8 animals per group; WT C57BL/6: n = 9–10 animals per group) containing the lesion center as well as consecutive rostral and caudal areas were analyzed, as previously described (Boato et al., 2010, Dooley et al., 2016, Geurts et al., 2015, Nelissen et al., 2013, Vangansewinkel et al., 2016). To quantify classically activated and alternatively activated microglia/macrophages at the lesion or graft site, we stained sections for MHC-II and ARG-1, respectively.…”

The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation?

“…IL-22 mediated protection and regeneration were also observed in experimental models of hepatic, pancreatic, and thymic injuries [72–75]. In addition, a mast cell-specific tryptase, mouse mast cell protease (mMCP) 6, directly cleaves fibronectin and collagen IV and, therefore, suppressed scars and promoted functional recovery after spinal cord injury [76]. Platelets contributed to liver regeneration by secreting serotonin in mice as well as humans [77, 78].…”

Modulation of inflammatory factors predicts the outcome following spinal cord injury

“…Neuroinflammation occurs almost immediately after spinal cord injury, including activation of immune cells and cytokines [6]. Studies have demonstrated that mast cells, bone marrow-derived macrophages, dendritic cells, type 2 congenital lymphocytes (ILC2S) and T cells might influence the outcome of spinal cord injury [7][8][9][10][11]. These cells release a large number of inflammatory factors (IL-1, IL-6, IL-8, IL-12, IFN-α, IFN-γ), chemokines(CXCL-1, CXCL-2), proteolytic enzymes and complement proteins when damage occurs [12,13] Among these cytokines, the proinflammatory mediators, reactive oxygen species, and NO often contribute to inflammation and aggravate the traumatic injury [14].…”