Mechanism Of PI3K Signaling In Regulating Treg's Homeostasis In Pulmonary Sarcoidosis

Sarcoidosis is a systemic granulomatous disease associated with Th1/regulatory T cells(Treg)paradigm.The feature of pulmonary sarcoidosis is characterized by a Th1/Th17/regulatory T cells(Tregs)-driven inflammatory process in lung,resulting in noncaseating granulomas containing CD4+ T cells.Tregs increase in both lung and peripheral blood,with damaged immunoregulatory function.The current study investigated the effects of IL33 or anti-IL23 antibody on restoring the homeostasis and functions of Tregs in mycobacterial superoxide dismutase A(SodA)-induced pulmonary sarcoidosis.IL33 or anti-IL23 antibody was administered to mice with late-stage pulmonary sarcoidosis.The levels of Th1/Th17/Tregs and Tregs' suppressive functions were detected by fluorescence activated cell sorting(FACS)analysis or qPCR.The expressions of key proteins in PI3K/Akt/mTOR and TGF-(3/Smad2/Smad3 signaling pathways were tested by western blot.IL33 administration was associated with the rebalance of Th1/Th2 and Tregs,as well as a superior suppressor activity of Tregs on effector T cells in sarcoidosis,probably through increasing ST2 expressions on Tregs,along with the suppression of PI3K/Akt/mTOR and TGF-?/Smad2/Smad3 signaling pathways.Small dose of anti-IL23 antibody independently improved Thl/Th2 bias,but had limited effects on the homeostasis and ST2 expressions on Tregs.These results suggested a major anti-inflammatory ability of IL33 to ameliorate the disturbance of Th1/Th2 and Tregs in pulmonary sarcoidosis,through the inhibiting PI3K signaling pathway and restoreing Tregs'homeostasis in pulmonary sarcoidosis.PI3K/Akt signaling,critical for maintaining Treg's homeostasis,is aberrantly activated in sarcoidosis patients.Encouranged by prior experimental data,here we tested the role of the PI3K inhibitors,LY294002 and BKM120,in immune modulation in experimental pulmonary sarcoidosis,concerning Th1/Th17/Treg immune profile detected by fluorescence-activated cell sorting analysis or qPCR,as well as the effect on Treg's suppressive functions.Our investigation showed abnormal activation of PI3K/Akt signaling both in lung and Treg in pulmonary sarcoidosis,along with decreased frequency and damaged function of Treg.Blockage of PI3K suppressed this signaling in Treg,rebalanced Th1/Treg,inhibited the production of inflammatory cytokines,and enhanced Treg's function.All these results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis.Thus,control of PI3K signaling have potential for therapeutic translation,and can be candidate for add-on drugs to treat pulmonary sarcoidosis or other Treg-homeostasis-relative autoimmune deseases.