Role Of Innate Immune Cells Research Articles

Decoding physiological and pathological roles of innate immune cells in eye diseases: the perspectives from single-cell RNA sequencing.

Single-cell RNA sequencing (scRNA-seq) has facilitated a deeper comprehension of the molecular mechanisms behind eye diseases and has prompted the selection of precise therapeutic targets by examining the cellular and molecular intricacies at the single-cell level. This review delineates the pivotal role of scRNA-seq in elucidating the functions of innate immune cells within the context of ocular pathologies. Recent advancements in scRNA-seq have revealed that innate immune cells, both from the periphery and resident in the retina, are actively engaged in various stages of multiple eye diseases. Notably, resident microglia and infiltrating neutrophils exhibit swift responses during the initial phase of injury, while peripheral monocyte-derived macrophages exhibit transcriptomic profiles akin to those of activated microglia, suggesting their potential for long-term residence within the retina. The scRNA-seq analyses have underscored the cellular heterogeneity and gene expression alterations within innate immune cells, which, while sharing commonalities, exhibit disease-specific variations. These insights have not only broadened our understanding of the cellular and molecular mechanisms in eye diseases but also paved the way for the identification of candidate targets for targeted therapeutic interventions. The application of scRNA-seq technology has heralded a new era in the study of ocular pathologies, enabling a more detailed appreciation of the roles that innate immune cells play across a spectrum of eye diseases.

An insight into the role of innate immune cells in breast tumor microenvironment.

The immune background of breast cancer is highly heterogeneous and the immune system of the human body plays a dual role by both promoting and suppressing its progression. Innate immune cells are the first line of defense in the immune system and impart protection by identifying and interacting with foreign pathogens and cancer cells. Different innate immune cells like natural killer cells, macrophages, dendritic cells, and myeloid suppressor cells take part in hosting the cancer cells. Autophagy is another key component inside the tumor microenvironment and is linked to the disintegration and recycling of cellular components. Within the tumor microenvironment autophagy is involved with Pattern Recognition Receptors and inflammation. Various clinical studies have shown prominent results where innate immune cells and autophagy in combination are used for pathogen as well as cancer cell clearance. However, it is necessary to comprehend the complex tumor microenvironment so that different therapeutic approaches can be developed to enhance the suppressive actions of the cells toward breast cancer cells. In this review article, the complex interaction between immune cells and breast cancer cells and their role in developing effective immunotherapies to improve patient outcomes are discussed in detail.

CD33 and SHP-1/PTPN6 Interaction in Alzheimer's Disease.

Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the CD33 locus. It has been determined that the risk variant associated with AD increases the expression of the large isoform of CD33 (CD33M) in innate immune cells and alters its biological functions. CD33 is thought to signal via the interaction of its ITIM motif and the protein tyrosine phosphatase, SHP-1. Here, we utilize different molecular and computational approaches to investigate how AD-associated genetic variation in CD33 affects its interaction with SHP-1 in human microglia and microglia-like cells. Our findings demonstrate a genotype-dependent interaction between CD33 and SHP-1, which may functionally contribute to the AD risk associated with this CD33 variant. We also found that CD33-PTPN6 (SHP-1) gene-gene interactions impact AD-related traits, while CD33-PTPN11 (SHP-2) interactions do not.

Innate Immune Cells in Melanoma: Implications for Immunotherapy.

The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy.

The Roles of Innate Immune Cells in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by recurrent eczematous lesions and severe pruritus. The economic burden and time penalty caused by the relapse of AD reduce patients' life quality. AD has complex pathogenesis, including genetic disorders, epidermal barrier dysfunction, abnormal immune responses, microbial dysbiosis of the skin, and environmental factors. Recently, the role of innate immune cells in AD has attracted considerable attention. This review highlighted recent findings on innate immune cells in the onset and progression of AD. Innate immune cells play essential roles in the pathogenesis of AD and enough attention should be given for treating AD from the perspective of innate immunity in clinics.

Structural properties of immune complexes formed by viral antigens and specific antibodies shape the inflammatory response of macrophages

Data on the course of viral infections revealed severe inflammation as a consequence of antiviral immune response. Despite extensive research, there are insufficient data on the role of innate immune cells in promoting inflammation mediated by immune complexes (IC) of viral antigens and their specific antibodies. Recently, we demonstrated that antigens of human polyomaviruses (PyVs) induce an inflammatory response in macrophages. Here, we investigated macrophage activation by IC. We used primary murine macrophages as a cell model, virus-like particles (VLPs) of PyV capsid protein as antigens, and a collection of murine monoclonal antibodies (mAbs) of IgG1, IgG2a, IgG2b subclasses. The inflammatory response was investigated by analysing inflammatory chemokines and activation of NLRP3 inflammasome. We observed a diverse pattern of chemokine secretion in macrophages treated with different IC compared to VLPs alone. To link IC properties with cell activation status, we characterised the IC by advanced optical and acoustic techniques. Ellipsometry provided precise real-time kinetics of mAb-antigen interactions, while quartz crystal microbalance measurements showed changes in conformation and viscoelastic properties during IC formation. These results revealed differences in mAb-antigen interaction and mAb binding parameters of the investigated IC. We found that IC-mediated cell activation depends more on IC characteristics, including mAb affinity, than on mAb affinity for the activating Fc receptor. IC formed by the highest affinity mAb showed a significant enhancement of inflammasome activation. This may explain the hyperinflammation related to viral infection and vaccination. Our findings demonstrate that IC promote the viral antigen-induced inflammatory response depending on antibody properties.

Macrophages coordinate immune response to laser-induced injury via extracellular traps.

Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury. Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina. Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer. Our data offer novel insights into innate immunity's role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration.

A44 STAT1 ACTS IN INNATE IMMUNE CELLS TO PREVENT LIVER PATHOLOGY FOLLOWING ASYMPTOMATIC INTESTINAL VIRAL INFECTION

Abstract Background In the mammalian gut, interactions between the host and commensal organisms must be regulated to prevent damage and derive benefits from these organisms. While this regulation has been well-studied in the context of bacteria, much less is known about how commensal-like viruses in the intestine are managed by the host. Evidence demonstrates that viral commensals can provide benefits to the host which supplement those from bacteria. In mice, depletion of the intestinal virome enhances susceptibility to DSS-induced colitis. Contributions of the virome can also be studied using murine norovirus strain CR6 (CR6), which forms persistent asymptomatic infections in the gut; this infection protects mice from both C. rodentium- and DSS-induced colitis. Despite these benefits, host-encoded mechanisms regulating viral commensalism remain understudied. One host-encoded mechanism is STAT1. In contrast to asymptomatic infection in wild-type mice, STAT1-deficient mice (Stat1-/-) develop severe disease characterized by liver necrosis and weight loss following CR6 infection. However, it remains unknown how the loss of STAT1 leads to CR6-induced disease. Aims We aimed to define STAT1-dependent mechanisms of protection from CR6-induced liver pathology. Methods To determine the contribution of STAT1 in protection from CR6-induced disease, Stat1-/- and STAT1-sufficient Stat1+/- littermates were infected i.v. with CR6. At days 3, 5, and 7 days post-infection, clinical disease, cell-intrinsic viral loads, pathology, and cellular infiltration were assessed. Bone marrow chimeras were used to evaluate the requirement for hematopoietic vs non-hematopoietic STAT1 in preventing disease. Results By 3 days post-infection, myeloid cells infiltrate the liver of CR6-infected Stat1-/- mice. Clinical disease is associated with accumulation of myeloid cells, including macrophage and dendritic cells in the liver . Sorting of liver-infiltrating immune cell populations revealed that Stat1-/- macrophage have elevated viral loads compared to Stat1+/- littermates (Figure). Notably, CD11b+ cells were enriched within the necrotic lesions characteristic of CR6-induced disease. Consistent with a role for innate immune cells in disease, bone marrow-derived macrophage from Stat1-/- mice failed to control viral replication in vitro. Further, bone marrow chimeras revealed that STAT1 expression in hematopoietic cells is necessary and sufficient to prevent CR6-induced disease. Together, these data suggest that in the absence of STAT1, innate immune cells become heavily infected with CR6 and mediate severe liver pathology. Conclusions Our data suggest that STAT1 is critical to maintaining a commensal relationship with the intestinal virome. In the absence of STAT1, failure to restrict the replication of viral commensal CR6 in innate immune cells leads to severe liver pathology. STAT1-deficient innate immune cells fail to control viral replication. Stat1 -/- and Stat1+/- mice were infected i.v. with CR6. 5 days post-infection, macrophage, dendritic cell, neutrophil, and monocyte populations were isolated from the liver by FACS. Viral genome copies were quantified by RT-qPCR. LoD = Limit of Detection. Mann-Whitney U test, ** = p ampersand:003C 0.01. Funding Agencies CIHR

The role of innate immune cells in the colorectal cancer tumor microenvironment and advances in anti-tumor therapy research.

Innate immune cells in the colorectal cancer microenvironment mainly include macrophages, neutrophils, natural killer cells, dendritic cells and bone marrow-derived suppressor cells. They play a pivotal role in tumor initiation and progression through the secretion of diverse cytokines, chemokines, and other factors that govern these processes. Colorectal cancer is a common malignancy of the gastrointestinal tract, and understanding the role of innate immune cells in the microenvironment of CRC may help to improve therapeutic approaches to CRC and increase the good prognosis. In this review, we comprehensively explore the pivotal role of innate immune cells in the initiation and progression of colorectal cancer (CRC), alongside an extensive evaluation of the current landscape of innate immune cell-based immunotherapies, thereby offering valuable insights for future research strategies and clinical trials.

Avian Innate and Adaptive Immune Components: A Comprehensive Review

This article provides a comprehensive classical overview of the avian immune system, highlighting its unique components and functions. Although fundamentally similar to mammals, the avian immune system possesses distinct features in its tissues, cells, molecules, and genes. The study elaborates on the innate and adaptive immune components and critical functions in birds, detailing and artistically drawing the various organs such as the Bursa of Fabricius, thymus, spleen, and Harderian gland and cells involved in immunity. It discusses the role of innate immune cells and molecules along with the significance of B-and T lymphocytes immunoglobulins, antigen-presenting cells (APCs), especially macrophages and dendritic cells (DCs) and their related cytokines, including interleukins (ILs), emphasizing their crucial role in adaptive immunity especially activating various T lymphocytes. The article also underscores the complexity and efficiency of the avian immune system in combating pathogens and highlights the evolutionary adaptations that distinguish those from mammalian immune systems. This knowledge contributes to a better understanding of avian immunology and should go beyond this classical immune system, which is vital for improving disease management and vaccination strategies in birds.

Implications for neutrophils in cardiac arrhythmias.

Cardiac arrhythmias commonly occur as a result of aberrant electrical impulse formation or conduction in the myocardium. Frequently discussed triggers include underlying heart diseases such as myocardial ischemia, electrolyte imbalances, or genetic anomalies of ion channels involved in the tightly regulated cardiac action potential. Recently, the role of innate immune cells in the onset of arrhythmic events has been highlighted in numerous studies, correlating leukocyte expansion in the myocardium to increased arrhythmic burden. Here, we aim to call attention to the role of neutrophils in the pathogenesis of cardiac arrhythmias and their expansion during myocardial ischemia and infectious disease manifestation. In addition, we will elucidate molecular mechanisms associated with neutrophil activation and discuss their involvement as direct mediators of arrhythmogenicity.

Dual-Targeting Nanovesicles Carrying CSF1/CD47 Identified from Single-Cell Transcriptomics of Innate Immune Cells in Heart Transplant for Alleviating Acute Rejection.

Although immunosuppressive drugs for targeting T cells are the standard of care in acute transplantation rejection, the role of innate immune cells should not be ignored. Here, single-cell RNA sequencing (scRNA-seq) and flow cytometry are performed to reveal the dynamic changes of innate immune cells within the acute rejection time and find a significantly-increased presence of Ly6G- Ly6C+ inflammatory macrophages and decreased presence of neutrophils among all types of immune cells. Next, to further explore potential targets regulating Ly6G- Ly6C+ inflammatory macrophages, scRNA-seq is used to analyze the reciprocal signaling of both neutrophils and macrophages, along with the surface genes of macrophages. It is found that activating colony-stimulating factor 1/ colony-stimulating factor 1 receptor (CSF1/CSF1R) andcluster of differentiation 47/signal regulatory protein α (CD47/SIRPα) signaling may serve as a strategy to relieve Ly6G- Ly6C+ inflammatory macrophage-mediated early graft rejection. To investigate this hypothesis, CSF1/CD47 dual-targeting nanovesicles (NVs) derived from IFN-γ-stimulated induced pluripotent stem cell-derived mesenchymal stem cells ( iPSC-MSCs )are designed and constructed. It is confirmed that CSF1/CD47 NVs synergistically induce the differentiation of Ly6G- Ly6C- M2 inhibitory macrophages by the CSF1/CSF1R pathway, and inhibit the phagocytosis of inflammatory macrophages and inflammatory response by the CD47/SIRPα pathway, ultimately relieving immune rejection. This study highlights the power of dual-targeting CSF1/CD47 NVs as an immunosuppressant against early innate immune responses with the potential for broad clinical applications.

The Role of Immune Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology with limited treatment options. The role of the immune system in IPF has received increasing attention. Uncontrolled immune responses drive the onset and progression of IPF. This article provides an overview of the role of innate immune cells (including macrophages, neutrophils, mast cells, eosinophils, dendritic cells, nature killer cells, nature kill cells and γδ T cells) and adaptive immune cells (including Th1 cells, Th2 cells, Th9 cells, Th17 cells, Th22 cells, cytotoxic T cells, B lymphocytes and Treg cells) in IPF. In addition, we review the current status of pharmacological treatments for IPF and new developments in immunotherapy. A deeper comprehension of the immune system's function in IPF may contribute to the development of targeted immunomodulatory therapies that can alter the course of the disease.

313.9: Peripheral blood mononuclear cells transcriptomic profile reveals a more prominent role of innate immune cells in pancreas rejection

313.9: Peripheral blood mononuclear cells transcriptomic profile reveals a more prominent role of innate immune cells in pancreas rejection

Type I IFN Derived from Ly6Chi Monocytes Suppresses Type 2 Inflammation in a Murine Model of Atopic Dermatitis

The roles of innate immune cells, including eosinophils, basophils, and group 2 innate lymphoid cells, in atopic dermatitis (AD) have been well-documented, whereas that of monocytes, another component of the innate immunity, remains rather poorly understood, thus necessitating the topic of this study. In addition, cytokines and cellular pathways needed for the resolution of type 2 inflammation in AD need further investigation. Using a murine AD model, we report here that (i) Ly6Chi monocytes were rapidly recruited to the AD lesion in a CCR2-dependent manner, blockade of which exacerbated AD; (ii) type I IFN production is profoundly involved in this suppression because the blockade of it by genetic depletion or antibody neutralization exacerbated AD; and (iii) Ly6Chi monocytes operate through the production of type I IFN because Ly6Chi monocytes from Irf7-null mice, which lack type I IFN production, failed to rescue Ccr2-/- mice from severe AD upon adoptive transfer. In addition, invitro studies demonstrated type I IFN suppressed basophil expansion from bone marrow progenitor cells and survival of mature basophils. Collectively, our work suggests that Ly6Chi monocytes are the first and dominant inflammatory cells reaching AD lesions that negatively regulate type 2 inflammation through the production of type I IFN.

Rag1 Deficiency Impairs Arteriogenesis in Mice.

Increasing evidence suggests that lymphocytes play distinct roles in inflammation-induced tissue remodeling and tissue damage. Arteriogenesis describes the growth of natural bypasses from pre-existing collateral arteries. This process compensates for the loss of artery function in occlusive arterial diseases. The role of innate immune cells is widely understood in the process of arteriogenesis, whereas the role of lymphocytes remains unclear and is the subject of the present study. To analyze the role of lymphocytes, we induced arteriogenesis in recombination activating gene-1 (Rag1) knockout (KO) mice by unilateral ligation of the femoral artery. The lack of functional lymphocytes in Rag1 KO mice resulted in reduced perfusion recovery as shown by laser Doppler imaging. Additionally, immunofluorescence staining revealed a reduced vascular cell proliferation along with a smaller inner luminal diameter in Rag1 KO mice. The perivascular macrophage polarization around the growing collateral arteries was shifted to more pro-inflammatory M1-like polarized macrophages. Together, these data suggest that lymphocytes are crucial for arteriogenesis by modulating perivascular macrophage polarization.

CCR2 macrophage response determines the functional outcome following cardiomyocyte transplantation

BackgroundThe immune response is a crucial factor for mediating the benefit of cardiac cell therapies. Our previous research showed that cardiomyocyte transplantation alters the cardiac immune response and, when combined with short-term pharmacological CCR2 inhibition, resulted in diminished functional benefit. However, the specific role of innate immune cells, especially CCR2 macrophages on the outcome of cardiomyocyte transplantation, is unclear.MethodsWe compared the cellular, molecular, and functional outcome following cardiomyocyte transplantation in wildtype and T cell- and B cell-deficient Rag2del mice. The cardiac inflammatory response was assessed using flow cytometry. Gene expression profile was assessed using single-cell and bulk RNA sequencing. Cardiac function and morphology were determined using magnetic resonance tomography and immunohistochemistry respectively.ResultsCompared to wildtype mice, Rag2del mice show an increased innate immune response at steady state and disparate macrophage response after MI. Subsequent single-cell analyses after MI showed differences in macrophage development and a lower prevalence of CCR2 expressing macrophages. Cardiomyocyte transplantation increased NK cells and monocytes, while reducing CCR2−MHC-IIlo macrophages. Consequently, it led to increased mRNA levels of genes involved in extracellular remodelling, poor graft survival, and no functional improvement. Using machine learning-based feature selection, Mfge8 and Ccl7 were identified as the primary targets underlying these effects in the heart.ConclusionsOur results demonstrate that the improved functional outcome following cardiomyocyte transplantation is dependent on a specific CCR2 macrophage response. This work highlights the need to study the role of the immune response for cardiomyocyte cell therapy for successful clinical translation.

#4443 INNATE IMMUNE MEMORY DETERMINES LONG-TERM KIDNEY ALLOGRAFT SURVIVAL

Abstract Background and Aims Historically, transplant medicine has focused primarily on the adaptive immune system, while the role of innate immune cells in the complex graft-reactive immune response has been understudied. The recently emerging concept of “trained immunity” is of particular interest in this regard. Trained immunity is a phenomenon in which innate immune cells develop a long-lasting memory in response to an initial stimulus, thereby reprogramming cells for a stronger inflammatory response to future stimuli. We hypothesized that damage-associated molecular patterns (DAMPs), released during ischemia-reperfusion injury, and immunosuppressive medication can affect trained immunity, and investigated in a cohort of kidney transplant patients if trained immunity is associated with long-term allograft survival. Method An established in vitro trained immunity assay was used in which human peripheral blood mononuclear cells (PBMCs) were stimulated. After five days of rest, cells were restimulated with lipopolysaccharide (LPS), and IL-6 and TNF were measured in the supernatant as a readout of the trained immunity response (Fig. 1A). We tested a library of DAMPs, and immunosuppressive drugs commonly used in kidney transplantation, to determine their effect on trained immunity. Of 96 kidney transplant recipients, with a follow-up for graft survival >8 years, serum was obtained before- and one week after transplantation. Patient sera were used to stimulate healthy PBMCs in the trained immunity assay. The relationship between serum induced trained immunity and long-term allograft survival was analyzed by Kaplan-Meier and Cox regression analysis. Results We found that DAMPs can affect trained immunity, causing either an enhanced (HMGB1, histones, IL-1β) or suppressed (vimentin, ATP, and C1q) cytokine response after LPS restimulation (Fig. 1B). Prednisone and tacrolimus potently suppressed trained immunity (Fig. 1C). In the kidney transplant patient cohort, cells stimulated with patients’ serum showed considerable heterogeneity in the IL-6 and TNF production after LPS restimulation. The IL-6 and TNF response of cells stimulated with serum obtained one week post-transplantation was lower compared to cells stimulated with serum obtained before transplantation (Difference of 463 ± 428 pg/mL, p<0.001 for IL-6; 1215 ± 1078 pg/mL, p<0.001 for TNF). The trained immunity response to post-transplant obtained serum was strongly associated with long-term death-censored graft survival (p = 0.005 for IL-6 tertials, and p = 0.037 for TNF tertials in a Kaplan-Meier analysis), and remained significant after adjusting for potential confounders. Conclusion Trained immunity can be affected by stimulation with DAMPs, which are released during ischemia-reperfusion injury during transplantation, and by immunosuppressive drugs used in kidney transplantation. The net effect of patients' serum taken one week after transplantation, containing a mixture of DAMPs and immunosuppressive drugs, has a suppressive effect on trained immunity compared with patients' pre-transplant serum. Interestingly, the trained immunity response to post-transplant serum is strongly associated with long-term allograft survival. Thereby we have identified trained immunity as a novel and relevant immunological mechanism in organ transplantation.

Mettl3-m6A-Creb1 forms an intrinsic regulatory axis in maintaining iNKT cell pool and functional differentiation

N6-methyladenosine (m6A) methyltransferase Mettl3 is involved in conventional Tcell immunity; however, its role in innate immune cells remains largely unknown. Here, we show that Mettl3 intrinsically regulates invariant natural killer T (iNKT) cell development and function in an m6A-dependent manner. Conditional ablation of Mettl3 in CD4+CD8+ double-positive (DP) thymocytes impairs iNKT cell proliferation, differentiation, and cytokine secretion, which synergistically causes defects in B16F10 melanoma resistance. Transcriptomic and epi-transcriptomic analyses reveal that Mettl3 deficiency disturbs the expression of iNKT cell-related genes with altered m6A modification. Strikingly, Mettl3 modulates the stability of the Creb1 transcript, which in turn controls the protein and phosphorylation levels of Creb1. Furthermore, conditional targeting of Creb1 in DP thymocytes results in similar phenotypes of iNKT cells lacking Mettl3. Importantly, ectopic expression of Creb1 largely rectifies such developmental defects in Mettl3-deficient iNKT cells. These findings reveal that the Mettl3-m6A-Creb1 axis plays critical roles in regulating iNKT cells at the post-transcriptional layer.

The Role of Innate Immune Cells in Cardiac Injury and Repair: A Metabolic Perspective.

Recent technological advances have identified distinct subpopulations and roles of the cardiac innate immune cells, specifically macrophages and neutrophils. Studies on distinct metabolic pathways of macrophage and neutrophil in cardiac injury are expanding. Here, we elaborate on the roles of cardiac macrophages and neutrophils in concomitance with their metabolism in normal and diseased hearts. Single-cell techniques combined with fate mapping have identified the clusters of innate immune cell subpopulations present in the resting and diseased hearts. We are beginning to know about the presence of cardiac resident macrophages and their functions. Resident macrophages perform cardiac homeostatic roles, whereas infiltrating neutrophils and macrophages contribute to tissue damage during cardiac injury with eventual role in repair. Prior studies show that metabolic pathways regulate the phenotypes of the macrophages and neutrophils during cardiac injury. Profiling the metabolism of the innate immune cells, especially ofresident macrophages during chronic and acute cardiac diseases, can further the understanding of cardiac immunometabolism.