Prenatal programing of motivated behaviors:can innate immunity prime behavior?

Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu.Maternal exposure to high-energy dense diets can affect motivated behavior in the offs p ring leading to addiction and impaired sociability.A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring.While still under investigation,prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring.The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring.We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth.We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.

EZH2 identifies the precursors of human natural killer cells with trained immunity

Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the induction of trained immunity,identified the precursor subset for trained NK cells,and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.

Role of glycolysis in diabetic atherosclerosis

Diabetes mellitus is a kind of typical metabolic disorder characterized by elevated blood sugar levels.Atherosclerosis(AS)is one of the most common complications of diabetes.Modern lifestyles and trends that promote overconsumption and unhealthy practices have contributed to an increase in the annual incidence of diabetic AS worldwide,which has created a heavy burden on society.Several studies have shown the significant effects of glycolysis-related changes on the occurrence and development of diabetic AS,which may serve as novel therapeutic targets for diabetic AS in the future.Glycolysis is an important metabolic pathway that generates energy in various cells of the blood vessel wall.In particular,it plays a vital role in the physiological and pathological activities of the three important cells,Endothelial cells,macrophages and vascular smooth muscle cells.There are lots of similar mechanisms underlying diabetic and common AS,the former is more complex.In this article,we describe the role and mechanism underlying glycolysis in diabetic AS,as well as the therapeutic targets,such as trained immunity,microRNAs,gut microbiota,and associated drugs,with the aim to provide some new perspectives and potentially feasible programs for the treatment of diabetic AS in the foreseeable future.

Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia

Microglia,which are tissue-resident macrophages in the brain,play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis.Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria,and activates immune cells including microglia via Toll-like receptor 4 signaling.Lipopolysaccharide is generally known as an endotoxin,as administration of highdose lipopolysaccharide induces potent systemic inflammation.Also,it has long been recognized that lipopolysaccharide exacerbates neuroinflammation.In contrast,our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer’s disease pathology and suggested that neuroprotective microglia are involved in this phenomenon.Additionally,other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype.Therefore,lipopolysaccharide may not a mere inflammatory inducer,but an immunomodulator that can lead to neuroprotective effects in the brain.In this review,we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide.We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators,but instead must be described by their complex profile comprising various molecules related to inflammatory regulation,phagocytosis,neuroprotection,anti-apoptosis,and antioxidation.In addition,microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training.Immune training of neuroprotective microglia using lowdose lipopolysaccharide,especially through oral lipopolysaccharide administration,may represent an innovative prevention or treatment for neurological diseases;however more vigorous studies are still required to properly modulate these treatments.

GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease

Peripheral bacterial infections without impaired blood brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease(PD).Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation.However,how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown.In this study,we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS.GSDMD in peripheral myeloid cells promoted microglial immune training,thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner.Furthermore,pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models.Collectively,these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD.Based on these findings,GSDMD may serve as a therapeutic target for patients with PD.

Research progress in the off-target effects of Bacille Calmette-Guérin vaccine

Bacille Calmette-Guérin(BCG)vaccine is designed to provide protection against tuberculosis(TB).However,numerous epidemiological,clinical,and immunological studies have shown that BCG vaccination affects neonatal and infant mortality,which may be related to the reduction of TB-unrelated infections and diseases by BCG vaccine.We aimed to discuss the off-target effects of BCG vaccine on un-TB infections and diseases,as well as the potential mechanism and influencing factors.Literature was retrieved mainly from PubMed using medical subject headings"BCG,variations,and non-specific,heterologous or off-target".Studies have showed that BCG vaccination can prevent various heterologous infections,including respiratory tract infections,leprosy,and malaria,treat viral infections including human papillomavirus and herpes simplex virus infection as immunotherapy,and improve the immune responses as vaccine adjuvant.Besides,BCG vaccine can reduce the recurrence rate of non-muscle-invasive bladder cancer,and may provide protection against autoimmune diseases.These off-target effects of BCG vaccine are thought to be achieved by modulating heterologous lymphocyte responses or inducing trained immunity,which were found to be sex-differentiated and affected by the BCG vaccine strains,sequence or time of vaccination.

Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity

Virus-induced asthma is prevalent among children,but its underlying mechanisms are unclear.Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma.Nonetheless,the relationship between systemic virus infections,such as enterovirus infection,and the ensuing effects on allergic asthma development is unknown.Early-life enterovirus infection was correlated with higher risks of allergic diseases in children.Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period.Bone marrow-derived macrophages(BMDMs)from recovered EV-A71-infected mice showed sustained innate immune memory(trained immunity)that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites.Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice,which was inhibited by 2-deoxy-D-glucose(2-DG)pretreatment,suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.

Effects of Bacillus Calmette-Guerin on immunometabolism,microbiome and liver diseases

Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries.Moreover,metabolic diseases increase the risk of having infectious diseases.The treatment of metabolic disease may require a long-term strategy of taking multiple medications,which can be costly and have side effects.Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest.A growing body of evidence indicates that Bacillus Calmette-Guerin(BCG)offers protection against non-infectious diseases.The non-specific effects of BCG occur likely due to the induction of trained immunity.In this regard,understanding how BCG influences the development of chronic metabolic health including liver diseases would be important.This review focuses on research on BCG,the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome,immunity,and metabolism.

Advances in immune response to pulmonary infection:Nonspecificity,specificity and memory

The lung immune response consists of various cells involved in both innate and adaptive immune processes.Innate immunity participates in immune resistance in a nonspecific manner,whereas adaptive immunity effectively eliminates pathogens through specific recognition.It was previously believed that adaptive immune memory plays a leading role during secondary infections;however,innate immunity is also involved in immune memory.Trained immunity refers to the long-term functional reprogramming of innate immune cells caused by the first infection,which alters the immune response during the second challenge.Tissue resilience limits the tissue damage caused by infection by controlling excessive inflammation and promoting tissue repair.In this review,we summarize the impact of host immunity on the pathophysiological processes of pulmonary infections and discuss the latest progress in this regard.In addition to the factors influencing pathogenic microorganisms,we emphasize the importance of the host response.

Human immunology and immunotherapy:main achievements and challenges

The immune system is a fascinating world of cells,soluble factors,interacting cells,and tissues,all of which are interconnected.The highly complex nature of the immune system makes it difficult to view it as a whole,but researchers are now trying to put all the pieces of the puzzle together to obtain a more complete picture.The development of new specialized equipment and immunological techniques,genetic approaches,animal models,and a long list of monoclonal antibodies,among many other factors,are improving our knowledge of this sophisticated system.The different types of cell subsets,soluble factors,membrane molecules,and cell functionalities are some aspects that we are starting to understand,together with their roles in health,aging,and illness.This knowledge is filling many of the gaps,and in some cases,it has led to changes in our previous assumptions;e.g.,adaptive immune cells were previously thought to be unique memory cells until trained innate immunity was observed,and several innate immune cells with features similar to those of cytokine-secreting T cells have been discovered.Moreover,we have improved our knowledge not only regarding immune-mediated illnesses and how the immune system works and interacts with other systems and components(such as the microbiome)but also in terms of ways to manipulate this system through immunotherapy.The development of different types of immunotherapies,including vaccines(prophylactic and therapeutic),and the use of pathogens,m onodonal antibodies,recombinant proteins,cytokines,and cellular immunotherapies,are changing the way in which we approach many diseases,especially cancer.