Ragweed pollen-mediated IgE-independent release of biogenic amines from mast cells via induction of mitochondrial dysfunction.
Normal functions of mitochondria are required for physiological dynamics of cells, while their dysfunction contributes to development of various disorders including those of immune system. Here we demonstrate that exposure of mast cells to ragweed pollen extract increases production of H(2)O(2) via mitochondrial respiratory complex III. These mitochondrial ROS (mtROS) enhance secretion of histamine and serotonin from mast cells, but not enzymes such as beta-hexosaminidase, independently from FcvarepsilonRI-generated stimuli. The release of biogenic amines is associated with inhibition of secretory granules' H(+)-ATPase activity, activation of PKC-delta and microtubule-dependent motility, and it is independent from intracellular free Ca(2+) levels. To asses differences from IgE-mediated mast cell degranulation we show that mtROS decrease antigen-triggered beta-hexosaminidase release, while they are synergistic with antigen-induced IL-4 production in sensitized cells. Taken together, these data indicate that mitochondrial dysfunction can act independently from adaptive immunity, as well as augments Th2-type responses. Pharmacological maintenance of physiological mitochondrial function could have clinical benefits in prevention and treatment of allergic diseases.
Chodaczek
Grzegorz
G
Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, TX 77555, USA.
Bacsi
Attila
A
Dharajiya
Nilesh
N
Sur
Sanjiv
S
Hazra
Tapas K
TK
Boldogh
Istvan
I
D031164:Ambrosia / Q000737:chemistry; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects; D005434:Flow Cytometry; D006636:Histamine Release / Q000187:drug effects*; D007073:Immunoglobulin E / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011058:Pollen / Q000737:chemistry*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
D053119:Benzophenanthridines; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D015847:Interleukin-4; D012701:Serotonin; D007073:Immunoglobulin E; C016299:chelerythrine; D011493:Protein Kinase C; D025262:Vacuolar Proton-Translocating ATPases