PYRIN inflammasome activation abrogates IL1Ra expression providing a new mechanism underlying FMF pathogenesis.

OBJECTIVE Aberrant PYRIN inflammasome activity triggers FMF pathogenesis but the exact mechanism remains elusive and an obstacle to efficient treatment. Herein, we sought to identify PYRIN inflammasome specific mechanisms to improve FMF treatment and diagnostics in the future. METHODS PYRIN-specific protein secretion was assessed by proteome analysis in U937 derived macrophages, and specific findings were confirmed in PYRIN inflammasome activated monocytes from healthy blood donors (HD) and FMF patients, stratified by MEFV genotype categories corresponding to a suspected increasing FMF disease severity. RESULTS Proteome data revealed differential secretion pattern of IL1Rα from PYRIN and NLRP3 activated U937 derived macrophages, which was verified by ELISA and qPCR. Moreover, PYRIN activation significantly reduced IL1RN mRNA expression (p<0.001) and IL1Rα secretion (p<0.01) in healthy donor- and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine treated patients secreted lower amounts of IL1Rα as compared to healthy donors (p<0.05) and displayed decreased ratios of IL1Rα/IL1β (p<0.05), suggesting a reduced anti-inflammatory capacity. CONCLUSION Our data show an inherent lack of IL-1 receptor antagonist expression specific to PYRIN inflammasome activation, providing a new mechanism underlying FMF pathogenesis. The reduced IL1Rα levels in FMF monocytes suggest a diminished anti-inflammatory capacity potentially leaving FMF patient monocytes more sensitive to pro-inflammatory stimuli, regardless of being in colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL1Rα secretion in FMF patients, we suggest further investigations into IL1Rα dynamics and its potential implications for FMF treatment in the future.