Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase-stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.

Type 2 asthma, which accounts for the majority of asthma cases, is driven by Th2 cells that produce cytokines such as IL-4, IL-5, and IL-13. These cytokines promote several features of the disease, including eosinophilia, IgE production, bronchial hyperresponsiveness (BHR), mucus hypersecretion, and susceptibility to exacerbations. In contrast, type 2 asthma is characterized by the presence of neutrophils and reduced responsiveness to corticosteroids. In recent years, advances in our understanding of the distinct mechanisms at play in each asthma endotype have paved the way for the development of targeted therapies tailored to specific patient profiles. In this review, we first explore the underlying immunological mechanisms of various asthma endotypes. We also provide an overview of the different types of immunotherapies currently available to asthmatic patients and their clinical efficacy. Finally, we highlight emerging therapeutic strategies that hold promise for improving asthma management in the future.

Inflammasomes, particularly NLRC4, play crucial roles in immune responses to intracellular bacterial infections. However, gain-of-function mutations in NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). AIFEC patients who survive infancy typically have no further intestinal symptoms but retain susceptibility to macrophage activation syndrome (MAS). However, existing mouse models do not adequately replicate the inflammation observed in AIFEC patients. To better understand this, we developed a mouse model capable of conditional expression of the activating V341A mutation in NLRC4 (NLRC4-V341A KI). Global conversion to NLRC4-V341A at the germline resulted in symptoms closely mirroring those of human AIFEC, including severe infantile enterocolitis characterized by heightened intestinal inflammation, disrupted gut epithelium, compromised intestinal barrier integrity, severe diarrhea, and mortality within 10 days post-natally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1β, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, conditional conversion to NLRC4-V341A in adulthood caused systemic autoinflammation with only mild enterocolitis, mirroring AIFEC patients. Using this model, we demonstrated that IL-18 and TNF blockade effectively ameliorated AIFEC disease symptoms. Unexpectedly, glucose supplementation has emerged as a promising therapeutic strategy. These findings advance our understanding of AIFEC and illuminate the ways in which inflammasome activation contributes to very early onset inflammatory bowel disease (VEO-IBD) in the developing gut.

Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.

The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells. It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs. Here, we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells, a process regulated by hepatic stellate cells. Mechanistically, activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33, thereby maintaining the survival and immunosuppressive function of these neutrophils. The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation of β-oxidation and the stimulation of protumorigenic eicosanoid synthesis. In mouse models, targeting IL33 blocked neutrophil lipid synthesis, decreased the colonization of colorectal cancer cells in the liver, and enhanced the efficacy of immunotherapy. Overall, our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis. Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.

Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8 T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8 T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8 T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8 T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8 T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8 T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.

Microglia, the resident immune cells of the central nervous system, exhibit conserved developmental origins and core molecular signatures across vertebrate species, highlighting their crucial importance in the central nervous system. While homeostatic microglia maintain similar functions during phylogeny-such as immune surveillance, debris clearance, and synaptic pruning-their morphology, gene expression, and responses to stimuli remarkably vary by species. These differences reflect evolutionary divergence shaped by factors such as lifespan, regenerative potential, and immune architecture. This review integrates current findings from basic vertebrates such as zebrafish, rodents, and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution. Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.

Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage, but the role of interleukin-18 (IL-18), a cytokine associated with inflammasome activation, in modulating the T-cell response and autoimmune pathogenesis remains largely unclear. In this study, we detected high expression levels of the IL-18 receptor α chain (IL-18Rα) in murine and human Th17 cells. In culture, IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production, a phenotype of pathogenic Th17 (pTh17) cells. Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures. Mechanistically, IL-18 promoted Stat3 phosphorylation, which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production. In patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE), IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity. Moreover, the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren's syndrome (ESS) model mice and the renal tissues of lupus model mice. Furthermore, adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice, whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice. Together, our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development, indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.

Interleukin-1 (IL-1) was the first interleukin identified as a potent proinflammatory and multifunctional molecule involved in innate immune responses against microbes, as well as in conditions of tissue injury associated with infections and sterile conditions. IL-1 is part of a large system, the IL-1 system, comprising a family of ligands that act as agonists, receptor antagonists, and anti-inflammatory cytokines, as well as a family of receptors that includes signaling receptor complexes, decoy receptors and negative regulators. All the members of the IL-1 system are involved in inflammatory diseases, innate and adaptive immune responses, conditions associated with dysmetabolism, and cancer by affecting both the tumor microenvironment and cancer cells. The deregulated or excessive activation of several pathways associated with the IL-1 system may lead to detrimental inflammatory or immune reactions, including autoinflammatory, autoimmune, infectious and degenerative diseases. The negative regulation of the IL-1 system mediated by antagonists, decoy receptors, scavengers, and dominant-negative molecules plays nonredundant roles in controlling these conditions. Owing to the central role of IL-1 in the pathogenesis of inflammation-driven diseases, IL-1 blocking agents are approved for clinical use in several inflammatory conditions, and inhibitory agents for other members of the family are under development. Here, the complexity of the IL-1 system, the involvement of its different members in inflammation-driven diseases, and the therapeutic approaches to target members of pathways associated with these conditions are presented and discussed.

DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.

The inflammasome is an inflammatory signaling protein complex comprising a sensor protein, the adaptor protein ASC, and the cysteine protease caspase-1. Inflammasome sensor proteins are activated by microbial molecular patterns, endogenous self-derived damage signals, or exogenous environmental danger signals. Multiple inflammasomes that differ in their mechanisms of action and structural composition have been identified. The best characterized are the canonical NLRP1, NLRP3, NAIP-NLRC4, AIM2, and Pyrin inflammasomes and the noncanonical inflammasomes activated by caspase-4, caspase-5 or caspase-11. The lesser known inflammasomes are the NLRP6, NLRP7, NLRP9, NLRP10, NLRP12, CARD8, and MxA inflammasomes. Following inflammasome assembly, caspase-1 promotes the secretion of the proinflammatory cytokines IL-1β and IL-18, and pyroptosis is mediated by the membrane-disrupting proteins gasdermin D and ninjurin-1. These functional activities control innate and adaptive immune responses and the initiation, development, and progression of autoinflammation, cancer, infectious diseases, and neurodegenerative diseases. Understanding how inflammasomes respond to pathogens and sterile signals has refined our view of innate immunity and offered new therapeutic targets. In this review, we present a comprehensive overview of inflammasomes with an emphasis on the mechanistic principles that govern inflammasome formation. We also discuss the contributions of inflammasome activation to health and disease.

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in maintaining peripheral immune tolerance, but its mechanisms of action are highly complicated. Here, through the generation of a gene knock-in (KI) mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation, we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions. Interestingly, although both KO and KI Treg cells lost the ability to endocytose B7 molecules, the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals. Therefore, this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4. Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease, providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.

YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), yet its role in the pathogenesis of IBD, particularly in regulating immune responses in the gut mucosa, remains elusive. In this study, we demonstrated that YDJC expression is downregulated in inflamed mucosa, particularly in the CD4 T cells of IBD patients, and that Ydjc deficiency promotes CD4 T-cell proliferation and Th1 cell differentiation, thereby exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed that YdjcCD4 T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis. Consistently, treatment with key enzyme inhibitors targeting cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly suppressed CD4 T-cell proliferation and Th1 cell differentiation, thereby alleviating colitis in Ydjc mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., Hmgcr, Hmgcs1, and Cyp51). Therefore, our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation, suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.