Human mast cells secrete mitochondrial DNA that has inflammatory actions, is increased in the serum of children with autism, and is inhibited by luteolin (P3155)

Abstract

Abstract Mast cells participate through cytokine release in acquired and innate immunity, as well as inflammation involved in the pathogenesis of autism, atopic dermatitis and psoriasis, but the trigger is unknown. The peptide neurotensin (NT), found in the brain, gut and skin, is significantly increased in the serum of autistic children (n=20; 3 years old) along with significantly more mitochondrial (mt)DNA for Cytochrome B (p=0.0002), as compared to normally developing controls (n=12); these findings may characterize an autistic endophenotype since over 50% of patients have “allergic-like” symptoms and brain inflammation. Here we report that human LAD2 cells stimulated by NT and other triggers secrete mt components, including mtDNA, extracelluarly without cell death. Purified LAD2 mt components further trigger release of histamine, IL-1β, IL-8, PGD2 and TNF from mast cells, as well as vascular endothelial growth factor (VEGF) from human keratinocytes and human microvascular endothelial cells, and IL-6 from human microglial cells. When mtDNA from LAD2 cells was injected ip in rats, it was detected in rat serum within 4 hrs indicating that extravascular mtDNA could enter the systemic circulation. Pretreatment with the natural flavonoid luteolin inhibited mediator secretion in vitro. Such mt components secreted from stimulated live mast cells may act as “innate pathogens” contributing to the pathogenesis of inflammatory diseases and may serve as targets for novel treatments.