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

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Abstract

Background

Fibrotic 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.

Methods

APRIL 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.

Results

Expression 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.

Conclusions

Our data indicate that APRIL contributes to fibrotic scar formation after SCI by mediating the inflammatory response.

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Most cited references 17

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A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member April, Inhibits Tumor Cell Growth

Paul Rennert, Pascal Schneider, Teresa Cachero … (2000)

A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregulated in many tumors including colon and prostate carcinomas. Here we identify B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF receptor family, as receptors for APRIL. APRIL binds BCMA with higher affinity than TACI. A soluble form of BCMA, which inhibits the proliferative activity of APRIL in vitro, decreases tumor cell proliferation in nude mice. Growth of HT29 colon carcinoma cells is blocked when mice are treated once per week with the soluble receptor. These results suggest an important role for APRIL in tumorigenesis and point towards a novel anticancer strategy.

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Expression of pro-inflammatory cytokine and chemokine mRNA upon experimental spinal cord injury in mouse: an in situ hybridization study.

Jan Schwab, D Bartholdi (1997)

Injury to the spinal cord induces a complex cascade of cellular reactions at the local lesion area: secondary cell death and inflammatory reactions as well as scar and cavity formation take place. In order to investigate the molecular features underlying this local wounding response and to determine their pathophysiological implications, we studied the expression pattern of pro-inflammatory and chemoattractant cytokines in an experimental spinal cord injury model in mouse. We show by in situ hybridization that transcripts for the pro-inflammatory cytokines TNF alpha and IL-1 as well as the chemokines MIP-1alpha and MIP-1beta are upregulated within the first hour following injury. In this early phase, the expression of the pro-inflammatory cytokines is restricted to cells in the surroundings of the lesion area probably resident CNS cells. While TNF alpha is expressed in a very narrow time window, IL-1 can be detected in a second phase in a subset of polymorphonuclear granulocytes which immigrate into the spinal cord around 6 h. Message for the chemokines MIP-1alpha and beta is expressed in a generalized way in the grey matter of the entire spinal cord around 24 h and gets again restricted to the cellular infiltrate at the lesion site at 4 days following injury. Interestingly, our data suggest that resident CNS cells, most probably microglial cells, and not peripheral inflammatory cells, are the main source for cytokine and chemokine mRNAs. The defined cytokine pattern observed indicates that the inflammatory events upon lesioning the CNS are tightly controlled. The very early expression of pro-inflammatory cytokine and chemokine messages may represent an important element of the recruitment of inflammatory cells. Additional pathophysiological consequences of the specific cytokine pattern observed remain to be determined.

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Glial cell loss, proliferation and replacement in the contused murine spinal cord.

Jean Wrathall, Judith Lytle (2007)

Studies in the rat have shown that contusive spinal cord injury (SCI) results in devastating pathology, including significant loss of mature oligodendrocytes and astrocytes even in spared white matter. Subsequently, there is increased proliferation of endogenous NG2(+) cells, postulated to contribute to replacement of mature glia chronically, which is important for functional recovery. Studies of mechanisms that stimulate endogenous progenitor cells would be facilitated by using mouse models with naturally occurring and genetically engineered mutations. To determine whether the murine response is similar to that in the rat, we performed contusive SCI on adult female C57Bl/6 mice at the T8-9 level. Animals received bromodeoxyuridine injections in the first week following injury and were killed at 1, 3, 4, 7 or 28 days postinjury (DPI). The overall loss of macroglia and the temporal-spatial response of NG2(+) cells after SCI in the (C57Bl/6) mouse was very similar to that in the (Sprague-Dawley) rat. By 24 h after SCI nearly half of the macroglia in spared ventral white matter had been lost. Cell proliferation was increased at 1-7 DPI, peaking at 3-4 DPI. Dividing cells included NG2(+) cells and Cd11b(+) macrophages and microglia. Furthermore, cells dividing in the first week expressed markers of mature glia at 28 DPI. The similarities in endogenous progenitor cell response to SCI in the mouse and rat suggest that this is a fundamental injury response, and that transgenic mouse models may be used to further probe how this cellular response to SCI might be enhanced to improve recovery after SCI.

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Author and article information

Contributors

Lucy H. Funk: LFreer@med.miami.edu

Amber R. Hackett: A.Hackett@med.miami.edu

Mary Bartlett Bunge: MBunge@med.miami.edu

Jae K. Lee: 305-243-2646 , JLee22@med.miami.edu

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 20 April 2016

Publication date PMC-release: 20 April 2016

Publication date Collection: 2016

Volume: 13

Electronic Location Identifier: 87

Affiliations

[ ]Department of Neurological Surgery, Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL 33136 USA

[ ]Department of Cell Biology, University of Miami School of Medicine, Miami, FL 33136 USA

[ ]Department of Neurology, University of Miami School of Medicine, Miami, FL 33136 USA

[ ]University of Miami School of Medicine, 1095 NW 14th Terrace, LPLC 4-19, Miami, FL 33136 USA

Article

Publisher ID: 552

DOI: 10.1186/s12974-016-0552-4

PMC ID: 4839088

PubMed ID: 27098833

SO-VID: 40841b7a-93b5-4a91-80d5-3d2254ffe550

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 April 2016

Date accepted : 14 April 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R21NS082835

Award ID: R01NS009923

Award Recipient : Mary Bartlett Bunge Jae K. Lee

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: tnfsf13,glial scar,cell proliferation,fibrosis,baff,taci,bcma,baff-r

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: tnfsf13, glial scar, cell proliferation, fibrosis, baff, taci, bcma, baff-r

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

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Abstract

Background

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Most cited references 17

A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member April, Inhibits Tumor Cell Growth

Expression of pro-inflammatory cytokine and chemokine mRNA upon experimental spinal cord injury in mouse: an in situ hybridization study.

Glial cell loss, proliferation and replacement in the contused murine spinal cord.

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