ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γplay key roles in the etiology of immune thrombocytopenia(ITP);however,it remains elusive how macrophage-mediated platelet clearance is regulated in ITP.Here,we report that adhesion and degranulation-protein adaptor protein(ADAP)restrains platelet phagocytosis by macrophages in ITP via modulation of signal transducer and activator of transcription 1(STAT1)-FcγR signaling.We show that ITP was associated with the underexpression of ADAP in splenic macrophages.Furthermore,macrophages from Adap^(−/−)mice exhibited elevated platelet phagocytosis and upregulated proinflammatory signaling,and thrombocytopenia in Adap^(−/−)mice was mitigated by the depletion of macrophages.Mechanistically,ADAP interacted and competed with STAT1 binding to importinα5.ADAP deficiency potentiated STAT1 nuclear entry,leading to a selective enhancement of FcγRI/IV transcription in macrophages.Moreover,pharmacological inhibition of STAT1 or disruption of the STAT1-importinα5 interaction relieved thrombocytopenia in Adap^(−/−)mice.Thus,our findings not only reveal a critical role for ADAP as an intracellular immune checkpoint for shaping macrophage phagocytosis in ITP but also identify the ADAP-STAT1-importinα5 module as a promising therapeutic target in the treatment of ITP.

A continuous simulation of Holocene effective moisture change represented by variability of virtual lake level in East and Central Asia

The fluctuation of a single lake level is a comprehensive reflection of water balance within the basin, while the regional consistent fluctuations of lake level can indicate the change of regional effective moisture. Previous researches were mainly focused on reconstructing effective moisture by multiproxy analyses of lake sediments. We carried out a series of experiments, including a transient climate evolution model, a lake energy balance model and a lake water balance model to simulate continuous Holocene effective moisture change represented by variability of virtual lake level in East and Central Asia.The virtual lake level, area, water depth and salinity are not equivalent to actual values, but we estimated relative changes of the regional effective moisture. We also explored the driving mechanisms of effective moisture change in different geographical regions. Our results indicated that gradually falling effective moisture during the Holocene in northern China was due to the combined effects of high lake evaporation caused by longwave and shortwave radiation, and low precipitation caused by reductions of summer solar insolation. A decline in effective moisture through the Holocene in the Tibetan Plateau and southern Central Asia resulted from decreased precipitation because of the weakening of the Asian summer monsoon. Increased precipitation induced by the strengthening of the westerly circulation contributed to the effective moisture rise during the Holocene in northern Central Asia.