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Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model

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Abstract

Stromal cell-derived factor-1 alpha (SDF-1a) or CXCL12 is an important cytokine with multiple functions in the brain during development and in adulthood. The inflammatory response initiated by spinal cord injury (SCI) involves the processing of interleukin-1beta (IL-1ß) and IL-18 mediated by caspase-1 which is under the control of an intracellular multiprotein complex termed inflammasome. Using an SCI rat model, we found improved functional long-term recovery which is paralleled by a reduction of apoptosis after intrathecal treatment with SDF-1a. An intriguing aspect is that SDF-1a changed the number of neuroinflammatory cells in the damaged area. We further examined the cellular localization and sequential expression of several inflammasomes during SCI at 6 h, 24 h, 3 days, and 7 days as well as the role of SDF-1a as a regulatory factor for inflammasomes. Using 14-week old male Wistar rats, spinal cord contusion was applied at the thoracic segment 9, and animals were subsequently treated with SDF-1a via intrathecal application through an osmotic pump. SCI temporally increased the expression of the inflammasomes NLRP3, ASC, the inflammatory marker tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1β) and IL-18. SDF-1a significantly reduced the levels of IL-18, IL-1b, TNF-a, NLRP3, ASC, and caspase-1. Immunofluorescence double-labeling demonstrated that microglia and neurons are major sources of the ASC and NLRP3 respectivley. Our data provide clear evidence that SCI stimulates a complex scenario of inflammasome activation at the injured site and that SDF-1a-mediated neuroprotection presumably depends on the attenuation of the inflammasome complex.

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Acknowledgments

This work was supported by an internal START grant from the Medical Clinic (UKA) of the RWTH Aachen University (A. Zendedel).

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Statement

All animals used in this study were housed under specific pathogen-free conditions and with access to standard rodent diet and tap water ad libitum. All experiments were conducted in conformance with the NIH Guidelines for the Care and Use of Laboratory Animals.

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    Authors and Affiliations

    1. Institute of Neuroanatomy, RWTH Aachen University, 52074, Aachen, Germany

      Adib Zendedel, Sonja Johann, Markus Kipp & Cordian Beyer

    2. Department of Anatomical Sciences, Faculty of Medicine, Gilan University of Medical Sciences, Rasht, Iran

      Adib Zendedel

    3. School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

      Soraya Mehrabi

    4. Department of Anatomy and Neuroscience, Cellular and Molecular Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

      Mohammad-taghi Joghataei

    5. Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

      Gholamreza Hassanzadeh

    6. Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, Germany

      Markus Kipp

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    Correspondence to Adib Zendedel.

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    Adib Zendedel and Sonja Johann contributed equally to this work.

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    Zendedel, A., Johann, S., Mehrabi, S. et al. Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model. Mol Neurobiol 53, 3063–3075 (2016). https://doi.org/10.1007/s12035-015-9203-5

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