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PACAP/PAC1 Regulation of Inflammation via Catecholaminergic Neurons in a Model of Multiple Sclerosis

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Abstract

The sympathetic nervous system (SNS) serves to maintain homeostasis of vital organ systems throughout the body, and its dysfunction plays a major role in human disease. The SNS also links the central nervous system to the immune system during different types of stress via innervation of the lymph nodes, spleen, thymus, and bone marrow. Previous studies have shown that pituitary adenylate cyclase-activating polypeptide (PACAP, gene name adcyap1) exhibits anti-inflammatory properties in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Because PACAP is known to regulate SNS function, we hypothesized that part of the immunoprotective action of PACAP is due to its neuromodulatory effects on sympathetic neurons. To examine this, we used an inducible, targeted approach to conditionally disrupt not only the PACAP-preferring PAC1 receptor gene (adcyap1r1) in dopamine β-hydroxylase-expressing cells, which includes postganglionic sympathetic neurons, but also catecholaminergic neurons in the brain and adrenomedullary chromaffin cells. In contrast to our previous EAE studies using PACAP global knockout mice which developed severe and prolonged EAE, we found that mice with conditional loss of PAC1 receptors in catecholaminergic cells developed a delayed time course of EAE with reduced helper T cell type 1 (Th1) and Th17 and enhanced Th2 cell polarization. At later time points, similar to mice with global PACAP loss, mice with conditional loss of PAC1 exhibited more severe clinical disease than controls. The latter was associated with a reduction in the abundance of thymic regulatory T cells (Tregs). These studies indicate that PAC1 receptor signaling acts in catecholaminergic cells in a time-dependent manner. At early stages of disease development, it enhances the ability of the SNS to polarize the Th response towards a more inflammatory state. Then, after disease is established, it enhances the ability of the SNS to dampen the inflammatory response via Tregs. The lack of concordance in results between global PACAP KO mice and mice with the PAC1 deletion targeted to catecholaminergic cells during early EAE may be explained by the fact that PACAP acts to regulate inflammation via multiple receptor subtypes and multiple targets, including inflammatory cells.

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  • 26 October 2018

    The original version of this article unfortunately contained mistakes. The captured article title and corresponding author were incorrect.

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Acknowledgements

We would like to thank Dr. Hermann Rohrer (Max Planck Institute for Brain Research, Frankfurt, Germany) for the DβH-CreER mouse line and Dr. Anton Maximov (Scripps Research Institute, La Jolla, CA, USA) for the Ai9 reporter mouse line.

Funding

This project received support from the National Multiple Sclerosis Society (RG 1501-02646), the Cousins Center for Psychoneuroimmunology, UCLA Semel Institute, and the NIH/NCATS UCLA CTSI (Grant Number UL1TR000124). The latter award helped fund the generation of the PAC1flox/flox DβH-CreER mice.

Microscopy and cryosectioning was performed using instruments made available through the UCLA Intellectual and Developmental Disabilities Research Center (IDDRC) Core. The IDDRC is supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health (5U54HD087101-03) and is an Organized Research Unit supported by the Jane and Terry Semel Institute for Neuroscience and Human Behavior.

Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697 and by the JCCC, the UCLA AIDS Institute, the David Geffen School of Medicine at UCLA, the UCLA Chancellor’s Office, and the UCLA Vice Chancellor’s Office of Research.

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  1. Semel Institute for Neuroscience and Human Behavior/Neuropsychiatric Institute, Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA, USA

    Christina Van, Michael C. Condro, Kenny Lov, Ruoyan Zhu, Patrick T. Ricaflanca, Henly H. Ko, Anna L. Diep, Anh Q. Hoang & James A. Waschek

  2. Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA

    Christina Van

  3. Center for Ulcer Research and Education (CURE): Digestive Diseases Research Center, University of California, Los Angeles, Los Angeles, CA, USA

    Joseph Pisegna

  4. Max Planck Institute for Brain Research, Frankfurt, Germany

    Hermann Rohrer

  5. Institute for Clinical Neuroanatomy, Goethe University, Frankfurt, Germany

    Hermann Rohrer

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  1. Christina Van
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The original version of this article was revised: The captured Article Title and corresponding author are incorrect. Full information regarding the corrections made can be found in the correction for this article.

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Van, C., Condro, M.C., Lov, K. et al. PACAP/PAC1 Regulation of Inflammation via Catecholaminergic Neurons in a Model of Multiple Sclerosis. J Mol Neurosci 68, 439–451 (2019). https://doi.org/10.1007/s12031-018-1137-8

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