Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine

Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomodulatory properties.It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5-50%in the ongoing clinical trials.It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs.We found that the MSC therapeutic preparation in the present study had about 5%dead MSCs(DMSCs),characterized by apoptotic cells.Namely,1×10^(6) MSCs in the preparation contained about 5×10^(4) DMSCs.We found that the treatment with even 5×10^(4) DMSCs alone had the equal therapeutic effects as with 1×10^(6) MSCs.This protective effect of the dead MSCs alone was confirmed in four mouse models,including concanavalin A(ConA)-and carbon tetrachloride(CCI4)-induced acute liver injury,LPS-induced lung injury and spinal cord injury.We also found that the infused MSCs died by apoptosis in vivo.Furthermore,the therapeutic effect was attributed to the elevated level of phosphatidylserine(PS)upon the injection of MSCs or DMSCs.The direct administration of PS liposomes(PSLs)mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs.The Mer tyrosine kinase(MerTK)deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2(CCR2)reversed these protective effects of MSCs or DMSCs.These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the'living MSCs preparation"through releasing PS,which was further recognized by MerTK and participated in modulating immune cells.

Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Ischemic stroke represents a significant danger to human beings,especially the elderly.Interventions are only available to remove the clot,and the mechanism of neuronal death during ischemic stroke is still in debate.Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

The glycosylation in SARS-CoV-2 and its receptor ACE2

Coronavirus disease 2019(COVID-19),a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),has infected more than 235 million individuals and led to more than 4.8 million deaths worldwide as of October 52021.Cryo-electron microscopy and topology show that the SARS-CoV-2 genome encodes lots of highly glycosylated proteins,such as spike(S),envelope(E),membrane(M),and ORF3a proteins,which are responsible for host recognition,penetration,binding,recycling and pathogenesis.Here we reviewed the detections,substrates,biological functions of the glycosylation in SARS-CoV-2 proteins as well as the human receptor ACE2,and also summarized the approved and undergoing SARS-CoV-2 therapeutics associated with glycosylation.This review may not only broad the understanding of viral glycobiology,but also provide key clues for the development of new preventive and therapeutic methodologies against SARS-CoV-2 and its variants.

Structural and functional insights into sorting nexin 5/6 interaction with bacterial effector IncE

The endosomal trafficking pathways are essential for many cellular activities.They are also important targets by many intracellular pathogens.Key regulators of the endosomal trafficking include the retromer complex and sorting nexins(SNXs).Chlamydia trachomatis effector protein IncE directly targets the retromer components SNX5 and SNX6 and suppresses retromer-mediated transport,but the exact mechanism has remained unclear.We present the crystal structure of the PX domain of SNX5 in complex with IncE,showing that IncE binds to a highly conserved hydrophobic groove of SNX5.The unique helical hairpin of SNX5/6 is essential for binding,explaining the specificity of SNX5/6 for IncE.The SNX5/6–IncE interaction is required for cellular localization of IncE and its inhibitory function.Mechanistically,IncE inhibits the association of CI-MPR cargo with retromer-containing endosomal subdomains.Our study provides new insights into the regulation of retromer-mediated transport and illustrates the intricate competition between host and pathogens in controlling cellular trafficking.

The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response

Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,and phosphorylation;however,the underlying molecular mechanism is not fully understood.In this study,TRIM60 negatively regulated the formation and activation of the TAK1 signalosome.Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation,accompanied by elevated levels of proinflammatory cytokines but not IFN-I.Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination,resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways.The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562;substitution of these lysines with arginines abolished the SUMOylation of TAB2.In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L.monocytogenes infection.Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response,potentially paving the way for a new strategy to control antibacterial immune responses.

Correction: Spontaneous apoptosis of cells in therapeutic stemcell preparation exert immunomodulatory effects throughrelease of phosphatidylserine

After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the image of PBS group in Fig.7b in the main text.This duplication is a result of errors in figure assembly,and the correct Fig.5 is provided as follows.The key findings of the article are not affected by these corrections.