Abstract
The causative mutations for familial Mediterranean fever (FMF) are located in the MEFV gene, which encodes pyrin. Pyrin modulates the susceptibility to apoptosis via its PYD domain, but how the mutated versions of pyrin affect apoptotic processes are poorly understood. Spontaneous and induced rates of systemic neutrophil apoptosis as well as the levels of proteins involved in apoptosis were investigated ex vivo in patients with FMF using flow cytometry and RT-qPCR. The freshly collected neutrophils from the patients in FMF remission displayed a significantly larger number of cells spontaneously entering apoptosis compared to control (6.27 ± 2.14 vs. 1.69 ± 0.18%). This elevated ratio was retained after 24 h incubation of neutrophils in the growth medium (32.4 ± 7.41 vs. 7.65 ± 1.32%). Correspondingly, the mRNA level for caspase-3 was also significantly increased under these conditions. In response to the inducing agents, the neutrophils from FMF patients also displayed significantly elevated apoptotic rates compared to control. The elevated rates, however, can be largely explained by the higher basal ratio of apoptotic cells in the former group. Monitoring of several proteins involved in apoptosis has not revealed any conventional mechanisms contributing to the enhanced apoptotic rate of neutrophils in FMF. Although the exact molecular mechanisms of accelerated neutrophil apoptosis in FMF remain unknown, it may provide a protection against excessive inflammation and tissue damage due to a massive infiltration of neutrophils in the acute period of the disease.
Highlights
Familial Mediterranean fever [familial Mediterranean fever (FMF), MIM249100] is an autoinflammatory syndrome characterized by the recurrent episodes of fever and polyserositis
Apoptosis Rates in polymorphonuclear neutrophils (PMNs) Cells To evaluate the impact of FMF on the apoptotic processes in systemic PMNs, we measured the spontaneous rates of apoptosis in the cells from FMF patients compared to healthy subjects at 0, 3, and 24 h (Figure 1A)
The accelerated apoptosis of neutrophils in FMF seems rather contradictory to the conventional view that the cells in the pre-activated state have the extended lifespan
Summary
Familial Mediterranean fever [FMF, MIM249100] is an autoinflammatory syndrome characterized by the recurrent episodes of fever and polyserositis. Via the PYD domain, pyrin interacts with ASC (apoptosis-associated speck-like protein with a caspase recruitment domain), which overexpression is closely associated with inflammation and apoptosis [7, 8]. ASC is a central adaptor protein of the inflammasome, which mediates interaction of the pathogen recognition receptors and caspase 1 [9]. Despite the controversies regarding the exact mechanisms by which the mutated pyrin versions cause the episodes of sterile inflammation, it is believed that pyrin influences formation of yet unknown inflammasome, a multiprotein complex that mediates activation of caspase-1 and Apoptosis in familial Mediterranean fever subsequent secretion of IL-1β. In a number of studies, the NALP3 inflammasome complex has been implicated in the pathogenesis of FMF [6, 10]; whereas in other works, it has been associated with its own, pyrin inflammasome [11]
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