Tumor necrosis factor superfamily member APRIL contributes to fibrotic scar formation after spinal cord injury

Abstract

BackgroundFibrotic scar formation contributes to the axon growth-inhibitory environment that forms following spinal cord injury (SCI). We recently demonstrated that depletion of hematogenous macrophages led to a reduction in fibrotic scar formation and increased axon growth after SCI. These changes were associated with decreased TNFSF13 (a proliferation inducing ligand (APRIL)) expression, but the role of APRIL in fibrotic scar formation after SCI has not been directly investigated. Thus, the goal of this study was to determine the role of APRIL in fibrotic scar formation after SCI.MethodsAPRIL knockout and wild-type mice received contusive SCI and were assessed for inflammatory cytokine/chemokine expression, leukocyte infiltration, fibrotic scar formation, axon growth, and cell proliferation.ResultsExpression of APRIL and its receptor BCMA is increased following SCI, and genetic deletion of APRIL led to reduced fibrotic scar formation and increased axon growth. However, the fibrotic scar reduction in APRIL KO mice was not a result of changes in fibroblast or astrocyte proliferation. Rather, APRIL knockout mice displayed reduced TNFα and CCL2 expression and less macrophage and B cell infiltration at the injury site.ConclusionsOur data indicate that APRIL contributes to fibrotic scar formation after SCI by mediating the inflammatory response.

Mouse mast cell protease 4 suppresses scar formation after traumatic spinal cord injury

“…On the one hand, the glial scar contributes to protection of the spared neural tissues by establishing a boundary between damaged and healthy tissue, and by modulating the immune cells to promote the healing of the CNS tissue 50,51 . On the other hand, reduced fibrotic scar formation can lead to a decreased expression of tumor necrosis factor alpha 52 , which suggests that modulation of the fibrotic scar can also regulate the inflammatory response. Therefore we speculate that mMCP4 may modulate the interplay between the immune response and the scarring response in two ways: mMCP4 may reduce scarring following SCI by modulating inflammatory mediators 27,28 and it may suppress detrimental inflammatory processes in the injured CNS by cleaving and modifying scar-associated factors 53,54 .…”

Fibrotic Scar After Spinal Cord Injury: Crosstalk With Other Cells, Cellular Origin, Function, and Mechanism

“…Further investigations of the cytokine expression profile after the elimination of blood-derived macrophages showed that the expression of a profibrotic molecule, a proliferation-inducing ligand (APRIL), was significantly decreased, while the expression of antifibrotic molecules and bone morphogenetic proteins (BMPs) was significantly increased (Zhu et al, 2015a ). APRIL KO mice exhibit a reduction in the fibrotic scar area and an improvement in axonal regeneration after SCI, which may result from the reduced infiltration of B cells and macrophages (Funk et al, 2016 ). Therefore, the direct role of APRIL in the crosstalk between macrophages and fibroblasts requires further investigation, and BMPs and other potential molecular mechanisms should also be explored.…”

“…As before injury, Col1α1 + cells still do not express desmin, α-SMA, or other markers of perivascular cells, including NG2, Olig2, and GFAP (Soderblom et al, 2013 ). Thus, Col1α1 + cells are perivascular fibroblasts forming a fibrotic scar that specifically express PDGFRβ after SCI (Zhu et al, 2015b ; Funk et al, 2016 ).…”

RNAi‐mediated ephrin‐B2 silencing attenuates astroglial‐fibrotic scar formation and improves spinal cord axon growth

“…After SCI, the blood‐brain barrier is damaged, which induces a series of inflammatory responses and generates multiple inflammatory cytokines that in turn activate astrocytes and finally glial scar formation . Furthermore, up‐regulation of TGF‐β1 at the injured site would promote MFb to proliferate, invade the injured tissue, and secrete extracellular matrix (ECM) to form fibrous scars . Migration, arrangement, and demarcation of the two cell types are distinct, and they work together to form astroglial‐fibrotic scars .…”

“…28,29 Furthermore, up-regulation of TGF-β1 at the injured site would promote MFb to proliferate, invade the injured tissue, and secrete extracellular matrix (ECM) to form fibrous scars. 30,31 Migration, arrangement, and demarcation of the two cell types are distinct, and they work together to form astroglial-fibrotic scars. 32 Consequently, we established the in vitro astroglial-fibrotic scar model using TGF-β1 in the present study, despite that other cell types especially inflammation-related cells may also participate in the process.…”