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

Lucy H Funk,Amber R Hackett,Jae K Lee,Mary Bartlett Bunge

doi:10.1186/s12974-016-0552-4

Lucy H Funk, Amber R Hackett + Show 2 more

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https://doi.org/10.1186/s12974-016-0552-4

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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.

Highlights

Developing successful therapies for spinal cord injury (SCI) is a formidable medical challenge in part because of the axonal growth-inhibitory environment that develops following injury characterized by a glial and fibrotic scar [1]
Macrophages [8, 9], B cells, and activated T cells [10] express a proliferation inducing ligand (APRIL), and APRIL can interact with transmembrane activator and CAML interactor (TACI), B cell maturation antigen (BCMA), and heparan sulfate proteoglycan (HSPG) receptors [11,12,13,14]
We chose the 2-week time point because this is when the scar starts to mature and take its final shape. In both WT and APRIL KO mice, platelet-derived growth factor receptor beta (PDGFRβ)+ fibroblasts were present throughout the glial fibrillary acidic protein (GFAP)− region of the injury site with a dense boundary apposing the astroglial scar (Fig. 2a–f )

Summary

Introduction

Developing successful therapies for spinal cord injury (SCI) is a formidable medical challenge in part because of the axonal growth-inhibitory environment that develops following injury characterized by a glial and fibrotic scar [1]. Macrophages [8, 9], B cells, and activated T cells [10] express APRIL, and APRIL can interact with transmembrane activator and CAML interactor (TACI), B cell maturation antigen (BCMA), and heparan sulfate proteoglycan (HSPG) receptors [11,12,13,14] These receptors are shared with another closely related tumor necrosis factor (TNF) superfamily member B cell-activating factor (BAFF, TNFSF13b) [12, 13]. 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.

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