Hayes


Email

2260 Biochemical Sciences Building
440 Henry Mall
Madison, WI 53706-1544
USA

(608) 263-6387

   

Colleen E Hayes

           

Professor,
B.A., DePauw University;
Ph.D., The University of Michigan

      

Molecular mechanisms that regulate immune responses

We study mechanisms by which the sunlight-derived hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3, Fig. 1) regulates the animal model of the autoimmune, neurodegenerative disease multiple sclerosis (MS).  MS is a debilitating disease for which there is no known method of prevention or cure, and no universally effective treatment.  In MS, infiltrating autoreactive T lymphocytes and mononuclear cells cause focal destruction of myelin, axonal injury and loss, and oligodendrocyte loss, leading to progressive neurological dysfunction.  One of the most striking features of MS is the dramatic decrease in disease prevalence and severity with increasing sunlight exposure.  A decade ago, we proposed a novel explanation for this observation, hypothesizing that 1,25-(OH)2D3, which derives from vitamin D3 and ultimately from sunlight, inhibits MS by controlling the T cell-mediated autoimmune response that is pathogenic in MS.  Compelling evidence from many disciplines now supports this hypothesis.  We are investigating 1,25-(OH)2D3 synthesis in the central nervous system (CNS), and 1,25-(OH)2D3-mediated anti-inflammatory and neuro-protective mechanisms in mouse experimental autoimmune encephalomyelitis (EAE), a model of MS, in the expectation that novel mechanistic insights derived from EAE research will provide the scientific foundation for designing effective vitamin D3-based prevention and treatment strategies for MS.


Figure 1.  1,25-(OH)2D3 treatment reversed EAE.  Mice with severe EAE were treated with 1,25-(OH)2D3 or a placebo.  Three days later, the hormone-treated mice had significantly less spinal cord pathology (myelin is stained dark purple stained myelin in the spinal cord sections above) and had regained the ability to walk (data not shown).

We reported that 1,25-(OH)2D3 inhibits EAE induction and progression, and reverses established EAE (see Fig. 1). However, we do not know what factors govern 1,25-(OH)2D3 synthesis in the CNS, which cells are responsive to 1,25-(OH)2D3, and what the 1,25-(OH)2D3-responsive cells do to protect the CNS from autoimmune-mediated damage. These are the questions we seek to answer through the ongoing research projects in the lab.

The balance between 1,25-(OH)2D3 synthesis and degradation determines the accumulation of 1,25-(OH)2D3 in the CNS, and its coordination of defenses against autoimmune-mediated damage. Ongoing research in the lab is investigating interferon-γ (IFN-γ) mediated control of 1,25-(OH)2D3 synthesis, and how estrogen (E2) influences 1,25-(OH)2D3 turnover in the inflamed CNS. The goal is to identify the cells responsible for 1,25-(OH)2D3 synthesis and degradation, and the signal transduction pathways that control transcription of the two relevant genes, Cyp27b1 encoding the synthetic enzyme and Cyp24a1 encoding the degrading enzyme. To study IFN-γ-mediated control of 1,25-(OH)2D3 synthesis and EAE disease, we are comparing EAE disease in IFN-γ-knockout (ko) and wild-type (Wt) mice, and correlating it with CEBPβ activation and hormone synthesis in cells that have been flow-sorted from the CNS of these mice. To study E2-mediated control of 1,25-(OH)2D3 synthesis and EAE disease, we are comparing EAE disease in ovariectomized and sham-operated mice, with and without hormone replacement, and correlating it with 1,25-(OH)2D3 synthesis in the CNS and in CNS cell isolates. Studies to date support a model wherein IFN-γ stimulates 1,25-(OH)2D3 synthesis, and E2 slows 1,25-(OH)2D3 degradation, so the 1,25-(OH)2D3 accumulates and exerts powerful anti-inflammatory and neuro-protective effects in the CNS.

In order to respond to 1,25-(OH)2D3 , a cell must express the vitamin D receptor (VDR). Accordingly, ongoing research in the lab is investigating which cells in the inflamed CNS express the VDR and perform protective functions. We are using two complementary approaches, determining by immunohistochemistry and flow cytometry which cells express the VDR, and subsequently deleting the VDR in cells of particular lineages by genetic techniques to learn which VDR-expressing cells are essential for 1,25-(OH)2D3 -mediated inhibition of EAE.

Lastly, ongoing research in the lab is investigating the anti-inflammatory and neuro-protective mechanisms that 1,25-(OH)2D3 induces to prevent autoimmune-mediated damage in the CNS. One mechanism involves sensitization of infiltrating inflammatory cells to apoptotic signals from CNS-resident cells. A second mechanism involves enhancement of the neurotrophin-neurotrophin receptor system that supports development, differentiation, and maintenance of neuronal systems, neuronal plasticity, synaptic activity, and neurotransmitter-mediated activities.



    

 

 

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