Hariharan Subramanian, Ph.D.
Allergic diseases are among the major causes of illness and disability in the U.S which accounts for ~500,000 hospitalizations each year, and has an annual economic cost of over $20 billion. As the adverse impact of allergic diseases on public health continues to grow, there is an urgent need to develop novel approaches to treat these diseases.
Allergic diseases are caused by an overzealous immune response to allergens in which mast cells play critical roles. Mast cells are innate immune cells present in tissues that are commonly exposed to the external environment such as skin, oral and nasal cavities, trachea, lungs, and gastrointestinal tracts. They are activated primarily via two mechanisms; 1) antigen/allergen-induced crosslinking of immunoglobulin E (IgE)-bound Fcε receptors, and 2) agonist binding of G-protein-coupled receptors (GPCR) on cell surface. Activated mast cells rapidly release granules containing pro-inflammatory mediators such as histamines and leukotrienes and this event triggers the immediate symptoms associated with allergic diseases. Though the pathways that activate mast cells have been characterized, the molecular signals that regulate these pathways remain largely unknown. One of the goals of my laboratory is to identify the roles of signaling proteins (adapter molecules) that regulate mast cell activation via Fcε receptors and GPCR during allergic diseases.
Environmental pollutants and pre-exposure to certain viruses also potentiate allergic diseases. Recent reports have demonstrated that diesel exhaust particles (DEP) and certain viruses such as human respiratory syncytial virus (RSV) and rhinovirus can exacerbate allergic asthma in children. However the mechanism and the cellular components involved in viral exposure-induced asthma remain elusive. An important aspect of my research goal is to identify the mechanisms through which exposure to environmental pollutants and viruses amplify mast cell-mediated asthma. In summary, my research program aims to not only understand the mechanism of mast cell activation but also identify novel drug targets for mast cell-induced allergic diseases.
Two major approaches are used in the laboratory. First, we use mast cell-specific mouse models of allergic diseases to determine the roles of specific adapter molecules in regulating the pathophysiology of the disease. We also use primary bone marrow-derived human as well as mouse mast cells and perform cellular and biochemical assays to assess mast cell activation in vitro.
- Gupta, K., Subramanian, H., Ali, H. Modulation of host defense peptide-mediated human mast cell activation by LPS. Innate Immun. 2015; [Epub ahead of print].
Web link: http://www.ncbi.nlm.nih.gov/pubmed/26511058
- Gupta, K., Kotian, A., Subramanian, H., Daniell, H., Ali, H. Activation of human mast cells by retrocyclin and protegrin highlight their immunomodulatory and antimicrobial properties. Oncotarget. 2015; 6(30):28573-87
Web link: http://www.ncbi.nlm.nih.gov/pubmed/26378047
- Subramanian, H., Gupta, K., Parameswaran, N., Ali, H. Regulation of FceRI signaling in mast cells by G protein coupled receptor kinase 2 and its RH domain. J. Biol. Chem. 2014; 289(30):20917-927
Web link: http://www.ncbi.nlm.nih.gov/pubmed/24904059
- Subramanian, H., Gupta, K., Lee, D., Bayir, A.K., Ahn, H., Ali, H. β-defensins activate human mast cells via Mas-related Gene-X2 (MrgX2) J.Immunol. 2013; 191(1):345-52 (Featured “In This Issue” of J.Immunol.)
Web link: http://www.ncbi.nlm.nih.gov/pubmed/23698749
- Subramanian, H., Gupta, K., Ali, H. Roles for NHERF1 and NHERF2 on the regulation of C3a receptor signaling in human mast cells. PLoS One. 2012; 7(12):e51355
Web link: http://www.ncbi.nlm.nih.gov/pubmed/23284683
- Gupta, K., Subramanian, H., Klos, A., Ali, H. Phosphorylation of C3a receptor at multiple sites mediates desensitization, β-arrestin-2 recruitment and inhibition of NF-κB activity in mast cells. PLoS One. 2012; 7(10):e46369
Web link: http://www.ncbi.nlm.nih.gov/pubmed/23077507
- Subramanian, H., Gupta, K., Guo, Q., Price, R., Ali, H. MAS-Related gene X2 (MrgX2) as a novel Receptor for the antimicrobial Peptide, LL-37: Resistance to Receptor Phosphorylation and Desensitization. J. Biol. Chem. 2011; 286(52):44739-49
Web link: http://www.ncbi.nlm.nih.gov/pubmed/22069323
- Guo, Q, Subramanian, H., Gupta, K., Ali, H. Regulation of C3a receptor signaling in human mast cells by G Protein coupled receptor kinases. PLoS One. 2011; 6(7):e22559
Web link: http://www.ncbi.nlm.nih.gov/pubmed/21799898
- Kashem, S.W., Subramanian, H., Collington, S., Maggoti, P., Lambris, J.D., Ali, H. G protein coupled receptor specificity for C3a and compound 48/80-induced degranulation in human mast cells: roles of Mas-related genes MrgX1 and MrgX2. Eur. J. Pharm. 2011; 668(1-2):299-304
Web link: http://www.ncbi.nlm.nih.gov/pubmed/21741965
- Vibhuti, A., Gupta, K., Subramanian, H., Guo, Q., Ali, H. Distinct and shared roles of β-Arrestin-1 and β-Arrestin-2 on the regulation of C3a receptor signaling in human mast cells. PLoS One. 2011; 6(5):e19585
Web link: http://www.ncbi.nlm.nih.gov/pubmed/21589858
- Subramanian, H., Kashem, S.W., Collington, S.J., Qu, H., Lambris, J.D., Ali, H. PMX-53 as a dual CD88 antagonist and an agonist for Mas-Related Gene 2 (MrgX2) in human mast cells. Mol Pharmacol. 2011; 79(6):1005-13
Web link: http://www.ncbi.nlm.nih.gov/pubmed/21441599