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Loss of PPARα perpetuates sex differences in stroke reflected by peripheral immune mechanisms

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Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that plays a role in immune regulation. Because of its expression in cerebral tissue and immune cells, PPARα has been examined as an important regulator in immune-based neurological diseases. Many studies have indicated that pre-treatment of animals with PPARα agonists induces protection against stroke. However, our previous reports indicate that protection is only in males, not females, and can be attributed to different PPARα expression between the sexes. In the current study, we examine how loss of PPARα affects male and female mice in experimental stroke. Male and female PPARα knockout mice were subject to middle cerebral artery occlusion (MCAO) or sham surgery, and the ischemic (local) or spleen specific (peripheral) immune response was examined 96 h after reperfusion. We found that loss of PPARα perpetuated sex differences in stroke, and this was driven by the peripheral, not local, immune response. Specifically we observed an increase in peripheral pro-inflammatory and adhesion molecule gene expression in PPARα KO males after MCAO compared to females. Our data supports previous evidence that PPARα plays an important role in sex differences in the immune response to disease, including stroke.

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Abbreviations

PPARα:

Peroxisome proliferator-activated receptor alpha

MCAO:

Middle cerebral artery occlusion

Treg:

Regulatory T cell

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Acknowledgements

The authors wish to thank Gail Kent for assistance with manuscript submission. This work was supported by NIH/NINDS 5R01NS076013 (HO, JAS). This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Neuroimmunology Research, R&D-31, Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR, 97239, USA

    Abby L. Dotson, Ha Nguyen, Dustin Manning & Halina Offner

  2. Department of Neurology, Oregon Health & Science University, Portland, OR, USA

    Abby L. Dotson, Ha Nguyen, Dustin Manning & Halina Offner

  3. Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA

    Jianming Wang, Jian Liang, Julie A. Saugstad & Halina Offner

Authors
  1. Abby L. Dotson
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  2. Jianming Wang
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  3. Jian Liang
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  4. Ha Nguyen
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  5. Dustin Manning
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  6. Julie A. Saugstad
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  7. Halina Offner
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Correspondence to Halina Offner.

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Compliance with ethical standards

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Oregon Health & Science University’s Institutional Animal Care and Use Committee.

This article does not contain any studies with human participants performed by any of the authors.

Funding

This work was supported by NIH/NINDS 5R01NS076013 (HO, JAS). This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

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The authors declare that they have no conflict of interest.

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Dotson, A.L., Wang, J., Liang, J. et al. Loss of PPARα perpetuates sex differences in stroke reflected by peripheral immune mechanisms. Metab Brain Dis 31, 683–692 (2016). https://doi.org/10.1007/s11011-016-9805-2

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