Background/Purpose: TRAPS (Tumor necrosis factors receptor associated periodic fever syndrome) is an autosomal dominant autoinflammatory disease associated with missense mutations in TNFRSF1A (tumor necrosis factor receptor superfamily, member 1A) gene. Our laboratory has recently demonstrated a role for mitochondrial reactive oxygen species (ROS) in triggering the hyper-responsiveness characteristic of cells from TRAPS patients. When the level of ROS generation exceeds the anti-oxidant defense capacity of the cell, oxidative damage to macromolecules including DNA ensues. We have investigated the metabolic sources of mitochondrial ROS production and levels of oxidative stress in cells from TRAPS patients, and will test the ability of MitoQ, a mitochondrial-targeted anti-oxidant to ameliorate symptoms in TRAPS patients.

Methods: Peripheral blood mononuclear cells (PBMC) from TRAPS patients and mouse embryonic fibroblasts (MEFs) from mice engineered to express TNFR1 mutations were analyzed for mitochondrial  ROS production and quantification of oxidative DNA damage via the DNA adduct 8-oxo-guanine (by using flow cytometric  method for detection of mitochondrial superoxide  and 8-oxo-guanine). Blockers of fatty acid and glucose metabolism were used to investigate the fuels which favor ROS production and excess cytokine production in fibroblasts and myleloid cells from TRAPS patients and TNFR1 mutant mice.

Results: We previously showed that the increased inflammation in TRAPS is dependent on mitochondrial ROS rather than NADPH oxidases. Elevated levels of mitochondrial ROS were seen in cells from TRAPS patients and in mice with engineered TRAPS gene mutations. Monocytes from TRAPS patients but not from healthy donors showed significantly higher spontaneous mitochondrial ROS production.  Blockade of fatty acid vs. glucose metabolism showed that fatty acid metabolism favors excess mitochondrial respiratory capacity, ROS production, and heightened expression of inflammatory cytokines after LPS treatment.  Inhibition of mitochondrial ROS can reduce normal cytokine production and reverse hyperinflammatory responses in TRAPS .PBMC from TRAPS patients and MEFs from mice  harboring TRAPS associated TNFR1mutation have increased levels of oxidized DNA compared controls.Inhibition of mitochondrial ROS by Mito Q can reduce normal cytokine production and reverse hyperinflammatory responses in PBMC from TRAPS patients and MEFs from mouse with similar mutations.

Conclusion: Our data suggest that mitochondrial ROS production and 8-oxo-guanine  are increased in TRAPS patients and in mice engineered to express TNFR1 mutations compared with non-inflammatory controls. Pharmacological blockade of mitochondrial ROS by mitoQ reduces inflammatory cytokine production in vitro in TRAPS patients and mice with similar TNFR1 mutations. These findings suggest that mitochondrial ROS may be a novel therapeutic target for TRAPS patients. A phase 2 clinical therapeutic trial using Mito Q for TRAPS is planned.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/oxidative-stress-as-a-disease-marker-and-therapeutic-target-in-patients-with-tumor-necrosis-factor-receptor-associated-periodic-fever-syndrome/