Oxidative Stress and Mitochondria Are Involved in Anaphylaxis and Mast Cell Degranulation: A Systematic Review

Abstract

Anaphylaxis, an allergic reaction caused by the massive release of active mediators, can lead to anaphylactic shock (AS), the most severe and potentially life-threatening form of anaphylactic reaction. Nevertheless, understanding of its pathophysiology to support new therapies still needs to be improved. We performed a systematic review, assessing the role and the complex cellular interplay of mitochondria and oxidative stress during anaphylaxis, mast cell metabolism and degranulation. After presenting the main characteristics of anaphylaxis, the oxidant/antioxidant balance and mitochondrial functions, we focused this review on the involvement of mitochondria and oxidative stress in anaphylaxis. Then, we discussed the role of oxidative stress and mitochondria following mast cell stimulation by allergens, leading to degranulation, in order to further elucidate mechanistic pathways. Finally, we considered potential therapeutic interventions implementing these findings for the treatment of anaphylaxis. Experimental studies evaluated mainly cardiomyocyte metabolism during AS. Cardiac dysfunction was associated with left ventricle mitochondrial impairment and lipid peroxidation. Studies evaluating in vitro mast cell degranulation, following Immunoglobulin E (IgE) or non-IgE stimulation, revealed that mitochondrial respiratory complex integrity and membrane potential are crucial for mast cell degranulation. Antigen stimulation raises reactive oxygen species (ROS) production from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and mitochondria, leading to mast cell degranulation. Moreover, mast cell activation involved mitochondrial morphological changes and mitochondrial translocation to the cell surface near exocytosis sites. Interestingly, antioxidant administration reduced degranulation by lowering ROS levels. Altogether, these results highlight the crucial role of oxidative stress and mitochondria during anaphylaxis and mast cell degranulation. New therapeutics against anaphylaxis should probably target oxidative stress and mitochondria, in order to decrease anaphylaxis-induced systemic and major organ deleterious effects.

Keywords: anaphylactic shock; anaphylaxis; antioxidant; mast cells degranulation; mitochondria; oxidative stress; reactive oxygen species (ROS).

Figure 1

Illustration of the different organ dysfunctions during AS.

Figure 2

Illustration of mitochondrial structures. DNA deoxyribonucleic acid.

Figure 3

Illustration of mitochondrial ROS production and the deleterious effects of high production on mitochondrial functions. ADP: adenosine diphosphate; ATP: adenosine triphosphate; mPTP: mitochondrial permeability transition pore; mtDNA: mitochondrial DNA; O₂^•−: superoxide anion; OH^•: hydroxyl radical; OXPHOS: oxidative phosphorylation; I: complex I; II: complex II; III: complex III; IV: complex IV; cyt c: cytochrome c.

Figure 4

Flow-chart of the systematic review.

Figure 5

Major effects of AS on hemodynamic, cardiac and mitochondrial functions focused on cardiac dysfunctions, selected from the literature. (A) Hemodynamic impairments and increase in lactatemia in AS group between T0 and T15 min [5,94]. At T15 min we observe in AS group a (B) cardiac contractility decrease [86], a (C) cardiac mitochondrial impairment through complex II [5,86] and a (D) cardiac lipid peroxidation increase [5] as compared with CON group. MAP: mean arterial pressure, CO: cardiac output, LVSF: left ventricle shortening fraction, OXPHOS: oxidative phosphorylation, CON: control group, AS: shocked group, TBARs: thiobarbituric acid reactive substances.

Figure 6

Mitochondrial involvement and oxidative stress pathways implicated during mast cell stimulation. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca²⁺, calcium ion; CRAC, calcium release-activated channels; cyt c, cytochrome c; DAG, Diacylglycerol; FcεRI, high-affinity IgE receptor; Fyn, Src family kinase; I mitochondrial complex I; II mitochondrial complex II; III mitochondrial complex III; IV mitochondrial complex IV; IgE, immunoglobulin E; IP3, Inositol 1,4,5,-triphosphate; IP3R, inositol trisphosphate receptor; Lyn, Src family kinase; mtSTAT3, mitochondrial signal transducer and activator of transcription 3; mtMITF, mitochondrial microphthalmia associated-transcription factor; MRGPRX2, Mas-related G-protein coupled receptor member X2; mtROS, mitochondrial ROS; NOX, NADPH oxidase; PLCγ, phospholipase Cγ; PI3K, Phosphatidylinositol 3 kinase; PKC, Protein kinase C; ROS, Reactive Oxygen Species; SERCA, sarco/endoplasmic Ca²⁺-ATPase; Syk, Spleen tyrosine kinase; STIM, stromal interaction molecule; Syk, Spleen tyrosine kinase; TCA cycle, tricarboxylic acid cycle.