The RNA m^(6)A demethylase ALKBH5 drives emergency granulopoiesis and neutrophil mobilization by upregulating G-CSFR expression

Emergency granulopoiesis and neutrophil mobilization that can be triggered by granulocyte colony-stimulating factor(G-CSF)through its receptor G-CSFR are essential for antibacterial innate defense.However,the epigenetic modifiers crucial for intrinsically regulating G-CSFR expression and the antibacterial response of neutrophils remain largely unclear.N6-methyladenosine(m^(6)A)RNA modification and the related demethylase alkB homolog 5(ALKBH5)are key epigenetic regulators of immunity and inflammation,but their roles in neutrophil production and mobilization are still unknown.We used cecal ligation and puncture(CLP)-induced polymicrobial sepsis to model systemic bacterial infection,and we report that ALKBH5 is required for emergency granulopoiesis and neutrophil mobilization.ALKBH5 depletion significantly impaired the production of immature neutrophils in the bone marrow of septic mice.In addition,Alkbh5-deficient septic mice exhibited higher retention of mature neutrophils in the bone marrow and defective neutrophil release into the circulation,which led to fewer neutrophils at the infection site than in their wild-type littermates.During bacterial infection,ALKBH5 imprinted production-and mobilization-promoting transcriptome signatures in both mouse and human neutrophils.Mechanistically,ALKBH5 erased m^(6)A methylation on the CSF3R mRNA to increase the mRNA stability and protein expression of G-CSFR,consequently upregulating cell surface G-CSFR expression and downstream STAT3 signaling in neutrophils.The RIP-qPCR results confirmed the direct binding of ALKBH5 to the CSF3R mRNA,and the binding strength declined upon bacterial infection,accounting for the decrease in G-CSFR expression on bacteria-infected neutrophils.Considering these results collectively,we define a new role of ALKBH5 in intrinsically driving neutrophil production and mobilization through m^(6)A demethylation-dependent posttranscriptional regulation,indicating that m^(6)A RNA modification in neutrophils is a potential target for treating bacterial infections and neutropenia.

m^(6)A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration

Neutrophil migration into the site of infection is necessary for antibacterial innate defense,whereas impaired neutrophil migration may result in excessive inflammation and even sepsis.The neutrophil migration directed by extracellular signals such as chemokines has been extensively studied,yet the intrinsic mechanism for determining neutrophil ability to migrate needs further investigation.N6-methyladenosine(m^(6)A)RNA modification is important in immunity and inflammation,and our preliminary data indicate downregulation of RNA m^(6)A demethylase alkB homolog 5(ALKBH5)in neutrophils during bacterial infection.Whether m^(6)A modification and ALKBH5 might intrinsically modulate neutrophil innate response remain unknown.Here we report that ALKBH5 is required for antibacterial innate defense by enhancing intrinsic ability of neutrophil migration.We found that deficiency of ALKBH5 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture(CLP),and Alkbh5-deficient CLP mice exhibited higher bacterial burden and massive proinflammatory cytokine production in the peritoneal cavity and blood because of less neutrophil migration.Alkbh5-deficient neutrophils had lower CXCR2 expression,thus exhibiting impaired migration toward chemokine CXCL2.Mechanistically,ALKBH5-mediated m^(6)A demethylation empowered neutrophils with high migration capability through altering the RNA decay,consequently regulating protein expression of its targets,neutrophil migration-related molecules,including increased expression of neutrophil migration-promoting CXCR2 and NLRP12,but decreased expression of neutrophil migration-suppressive PTGER4,TNC,and WNK1.Our findings reveal a previously unknown role of ALKBH5 in imprinting migrationpromoting transcriptome signatures in neutrophils and intrinsically promoting neutrophil migration for antibacterial defense,highlighting the potential application of targeting neutrophil m^(6)A modification in controlling bacterial infections.

The cycloaddition reaction using visible light photoredox catalysis

In recent years, visible light photoredox catalysis has emerged as an important research area in synthesis. In this review, we describe the recent progress in the visible light induced cycloaddition reactions, including [2+2], [3+2], [4+2] and [2+2+2] cycloadditions, for the construction of four-, five- or six-membered cycles and polycycles. Furthermore, the mechanisms for these transformations are also discussed, in which the formation of the radicals is initiated by a visible light photoredox catalysis process.

Redox-triggered hydroarylation of o-(hydroxyalkyl)arylalkynes with arylsulfonyl chlorides using visible light catalysis

A new radical-mediated method for the synthesis of 1-(2-(1,2-diarylvinyl)phenyl)ethan-1-ones by the redox hydroarylation of o-(hydroxyalkyl)arylalkynes with arylsulfonyl chlorides is described. This visible light catalysis method proceeds via a sequence of the radical addition of aryl group across the C?C triple bond, protonation and redox reaction, and represents a new redox transformation reaction directed by a neighboring hydroxyl group.