A role of mitochondria in mast cell activation and possible involvement in auto-immunity.
Zhang, Bodi.
2011
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Abstract: Mast cells, derived from bone marrow, are key immune effector cells that cause allergic symptoms, regulate innate and acquired immunity, but are also involved in many autoimmune and inflammatory diseases. Mast cells participate in immune process by secreting granule-stored components, such as histamine, and de novo synthesized mediators, such as IL-6, 8 and 13 in response to allergic, ne... read moreuropeptide and environmental triggers. Mast cells are well known to be activated by aggregation of high affinity receptors for the immunoglobulin E during which most mediators are released with detrimental pathophysiological effects. However, the regulation of secretion of granule and non-granule stored mediators is poorly understood. We show that degranulation and secretion of granule-stored TNF but not non-granule stored de novo synthesis and release, of TNF from human cultured mast cells requires substantial mitochondrial-associated energy and calcium. We further show that degranulation by various triggers leads to rapid granule-stored TNF secretion and mitochondrial (mt) fission and translocation to sites of exocytosis. Extracellular calcium depletion prevents the mitochondrial translocation, while the calcium ionophore A23187 induces translocation, indicating the necessarily of calcium influx. The calcium-dependent calcineurin and Dynamin Related Protein1 (Drp1) which are critical for mitochondrial dynamics, are activated rapidly after SP stimulation. Reduction of Drp1 activity by its inhibitor MDIVI-1 and decrease of Drp1 expression using siRNA inhibit mitochondrial translocation, TNF secretion and degranulation. In addition, gene expression of calcineurin, Drp1 and SP is higher in skin biopsies from patients with Atopic Dermatitis (AD) as compared to biopsies from normal control. The results presented here show that mitochondria could be a novel regulator of mast cell activation. We also show that human mast cell degranulation leads to mitochondrial fission into small particles and mtDNA release extracellulary. Mitochondrial components are not normally found outside the cells. Mitochondria purified from cultured sarcoma and LAD2 cells stimulate mast cell degranulation and pro-inflammatory mediators' secretion. Increasing evidence indicates that autism may be associated with some immune dysregulation, and may have a neuroimmune component. We find that mtDNA (7s, Cytochrome B) is elevated in the serum of children with autism. Mitochondria-based drug discovery may be used for the treatment of inflammatory and autoimmune diseases.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Biochemistry.
Advisor: Theoharis Theoharides.
Committee: Larry Feig, Louis Shuster, John Castellot, and Susan Leeman.
Keywords: Biochemistry, Pharmacology, and Immunology.read less - ID:
- dz0112223
- Component ID:
- tufts:20635
- To Cite:
- DCA Citation Guide EndNote
