HIF-1αpromotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming

The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.

Dynamic immune recovery process after liver transplantation revealed by single-cell multi-omics analysis

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.

Human umbilical cord mesenchymal stem cells for psoriasis:a phase 1/2a,single-arm study

Psoriasis is a common,chronic immune-mediated systemic disease that had no effective and durable treatment.Mesenchymal stem cells(MSCs)have immunomodulatory properties.Therefore,we performed a phase 1/2a,single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs(UMSCs)in the treatment of psoriasis and to preliminarily explore the possible mechanisms.Seventeen patients with psoriasis were enrolled and received UMsC infusions.Adverse events,laboratory parameters,PASl,and PGA were analyzed.We did not observe obvious side effects during the treatment and 6-month follow-up.A total of 47.1%(8/17)of the psoriasis patients had at least 40%improvement in the PASl score,and 17.6%(3/17)had no sign of disease or minimal disease based on the PGA score.And the efficiency was 25%(2/8)for males and 66.7%(6/9)for females.After UMSC transplantation(UMSCT),the frequencies of Tregs and CD4^(+)memory T cells were significantly increased,and the frequencies of T helper(Th)17 and CD4^(+)naive T cells were significantly decreased in peripheral blood(PB)of psoriasis patients.And all responders showed significant increases in Tregs and CD4^(+)memory T cells,and significant decreases in Th17 cells and serum IL-17 level after UMsCT.And baseline level of Tregs in responders were significantly lower than those in nonresponders.In conclusion,allogeneic UMSCT is safe and partially effective in psoriasis patients,and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT.Trial registration Clinical Trials NCT03765957.

The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis

Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection.Glycolysis plays a role in maintaining the immune function of macrophages,which is crucial for severely septic patients.However,how the pathways that link glycolysis and macrophages are regulated is still largely unknown.Here,we provide evidence to support the function of KLF14,a novel Krüppel-like transcription factor,in the regulation of glycolysis and the immune function of macrophages during sepsis.KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis.Mechanistically,KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2.In addition,we confirmed that the expression of KLF14 was upregulated in septic patients.Furthermore,pharmacological activation of KLF14 conferred protection against sepsis in mice.These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.