Faculty Research Page
Assistant Professor of Immunology and Pathogenesis
The goal of our research is to understand the molecular mechanisms underlying the link between inflammation and neurodegenerative diseases, and to explore possibilities of intervention using Nuclear Receptor (NR)-mediated signaling and transcriptional control. In this context we focus to understand the physiology and pathology of microglia cells, a key cell type of immunity and inflammation in the central nervous system (CNS). We take an interdisciplinary approach employing concepts and techniques from of Immunology, Neurobiology and Endocrinology.
Microglia are the major resident immune cells in the CNS, where they constantly survey the microenvironment and produce factors that influence other surrounding glia cells and neurons. Microglia cells detect pathogens or tissue damaging, initiate inflammation and wound healing and thereby help to maintain the homeostasis in the CNS. However, deregulation of microglia-mediated immunity leads to chronic inflammation and is often associated with neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease.
To evaluate counter-measures to pathological inflammation in neurodegenerative diseases, we study signaling and transcriptional regulation of Nuclear Receptors (NRs). NRs comprise a large family of ligand-dependent transcription factors that can both activate and repress target genes. Several NR contribute to male and female specific gene expression and many of chronic inflammatory diseases exhibit sex dimorphism. This led us to study the Estrogen Receptors (ER), which is best known for its functions in female physiology. The two isoforms, ERa and ERb, are expressed in both females and males, and ligands other than the well-known 17b-estradiol are critical in regulating inflammation, maintaining the homeostasis in microglia and could be useful to intervene in neurodegenerative diseases.
Estrogen Receptor (ER)b
ERb is highly expressed in microglia and astrocytes. ERb can function as a transcriptional repressor or an activator dependent on which ligand is bound. Our current projects in this area aim to understand the molecular mechanism that underlies these opposite outcomes of ligand interaction. We are identifying ligand-dependent ERb binding epigenetic regulators such as enzymes that modify histones or remodel chromatin. This approach is complemented by genome-wide analysis of ERb-mediated changes in RNA expression (mRNA, small RNA, lincRNA and eRNA) and histone marks. In parallel studies we investigate how the generation endogenous ligands by 17b-hydroxysteroid dehydrogenases is regulated in microglia. Finally, we will address the physiological roles of the ERb receptor/ligand system in animal models of neurodegenerative diseases including Parkinson’s disease, HIV-associate neurocognitive disorders and Multiple Sclerosis.
Estrogen Receptor (ER)a
In contrast to ERb, ERa is highly expressed in macrophages. Macrophages are key players of systemic chronic inflammation including metabolic syndrome and type 2 diabetes (T2D). Aging and T2D are risk factors for Alzheimer’s disease (AD), however, little is known about interactions between systemic inflammation and neurodegenerative diseases. We aim to understand links between T2D and AD by studying ERa-mediated transcriptional regulation of inflammation in macrophages.
1. Saijo K, Collier JG, Li AC, Katzenellenbogen JA, Glass CK. (2011) “An ERb-CtBP transrepression pathway negatively regulates microglia-mediated inflammation.” Cell 145:584-95
2. Huang W, Ghisletti S, Saijo K, Gandhi M, Aouadi M, Tesz G, Zhang D, Yao J, Czech M, Goode BL, Rosenfeld MG, Glass CK (2011) “Coronin2A mediates actin-dependent de-repression of inflammatory response genes.” Nature 470:414-8
3. Klotz L, Burgdorf S, Dani I, Saijo K, Alferink J, Langhans B, Klockgether T, Frommer F, Cherrier M, Waisman A, Eberl G, Glass CK, Kurts C and Knolle P. (2009) "The nuclear receptor PPARg controls TH17 differentiation and suppresses TH17 dependent autoimmunity." J Exp Med 206: 2079-89
4. Saijo K, Winner B, Carson CC, Collier JG, Boyer L., Rosenfeld MG, Gage FH, Glass CK. (2009) " A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death." Cell 137: 47-59
5. Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, Glass CK, Hume DA, Kellie S, Sweet MJ. (2008) "Expression Analysis of G Protein-Coupled Receptors in Mouse Macrophages." Immunome Research 4:5
1. Saijo K, Crotti A, Glass CK (2013) “Regulation of microglia activation and de-activation by nuclear receptors.” GLIA 61:104-11
2. Saijo K,Glass CK, (2011) “Microglial cell origin and phenotypes in health and disease” Nature Reviews Immunology. 11:775-87
3. Saijo K, Crotti A, Glass CK (2010) “Nuclear receptors, Inflammation and Neurodegenerative Disease” Advances in Immunology 106:21-59
4. Glass CK, Saijo K. (2010) “Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cell.” Nature Reviews Immunology. 10:365-76
5. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) “Mechanisms underlying inflammation in neurodegeneration.” Cell 140:918-934
6. Glass CK, Saijo K. (2008) "Immunology: Oxysterols hold T cells in check." Nature 455:40-1
Photo Credit: Mark Hanson
Last Updated 2013-08-22