In this report, we show that CRH not only can augment allergic mast-cell release of VEGF, but can also induce FcεRI expression in these human mast cells. Our finding is specific, because the peptide substance P had been shown previously to decrease FcεRI gene expression , as also does lipopolysaccharide . These results could explain how stress may worsen allergy-like symptoms in patients with ASDs [6, 8, 21]. It has previously been shown that CRH can augment NT-induced VEGF release . Hence, CRH might augment both allergic and non-immune mast-cell activation. The mechanism of such augmentation was not known.
Increased anxiety seems to be present in at least a subgroup of patients with ASDs, who may also be more prone to stress . A comparison of 34 adults with autism and 20 controls, matched for age, gender, and intellectual ability, found that patients with ASDs were three times as anxious as controls, and were significantly less able to cope with stress . Acute stress can activate brain mast cells, an effect abolished by pretreatment with polyclonal antiserum to CRH . Subsequently, CRH was reported to activate brain mast cells and increase blood–brain barrier permeability in rodents [25, 26], particularly in brain areas containing mast cells . The direct effect of CRH was documented by intradermal administration leading to increased vascular permeability in rodents and humans, through activation of CRHR-1 .
We also found that sonicated mitochondrial components at (10 microgram/μl) stimulates VEGF release, which also augments allergic stimulation of VEGF release from human mast cells. At the present, we are not sure which mitochondrial components are responsible for VEGF release. They may include ATP, mtDNA, or formyl peptides found in mitochondria. VEGF is also known to stimulate mitochondrial biogenesis , suggesting a possible paracrine effect on secreted VEGF on the mitochondria of neighboring cells.
Several studies have reported mitochondrial dysfunction in autism , which may involved a subset of children with autism [31, 32]. Mitochondria are the primary energy-generating organelles in eukaryotic cells, and they participate in multiple intracellular processes, including calcium buffering . However, mitochondria were originally bacteria that became symbiotic with eukaryotic cells, and are typically prevented from being released extracellularly by autophagy . We previously found increased extracellular mtDNA in the serum of young children with autism . The present results indicate that extracellular mitochondria components can augment allergic mast-cell stimulation. This action may be in addition to any direct effect that mitochondrial components may have on the immune system. For instance, damage-associated mitochondrial pattern are able to activate Toll-like receptor 9 on human peripheral polymorphonuclear leukocytes, leading to release of interleukin-8 .
Given that ASDs has been associated with brain inflammation and oxidative stress [1, 3, 36], we investigated the effect of the flavone luteolin, which has anti-inflammatory and anti-oxidant properties . We found that luteolin 100 μmol/l was able to inhibit the augmenting effect at mitochondria on allergic human mast-cell activation. We used this concentration because it had been previously shown to cause maximal inhibition of mast cells and mast-cell-dependent stimulation of activated T cells . Luteolin also blocks methyl mercury-induced VEGF release from human mast cells . Myricetin, the structural analog of luteolin, can also inhibit mast-cell activation , and methyl mercury-induced mitochondrial dysfunction . Luteolin also blocks activated peripheral blood mononuclear cells from patients with the inflammatory brain disease multiple sclerosis . A new luteolin-containing dietary supplement was recently shown to have significant benefit in children with ASDs . Luteolin may therefore be useful for the treatment of brain inflammation [40, 42].