Neutrophils play a dual role in inflammatory bowel diseases (IBD), contributing to both host defense and tissue damage. Among them, CXCR4+CD62Llo aged neutrophils have been implicated in chronic inflammation, though their precise involvement in the pathogenesis of IBD remains unclear. This study aimed to explore the functional characteristics and therapeutic potential of aged neutrophils in IBD. Samples of peripheral blood and colonic biopsies from 61 patients with IBD (47 with active disease, 14 with inactive disease) and 36 healthy controls were analyzed to quantify aged neutrophils. Flow cytometry, immunofluorescence, and neutrophil-peripheral blood mononuclear cell co-culture assays were used to assess their function. The therapeutic effects of the CXCR4 antagonist AMD3100 were tested in a dextran sulfate sodium-induced acute colitis model. Our results demonstrated a marked accumulation of aged neutrophils in both peripheral blood and inflamed intestinal tissues of patients with active IBD, and their abundance was positively correlated with disease severity. Functionally, these cells displayed elevated β-galactosidase activity, heightened reactive oxygen species generation, enhanced formation of neutrophil extracellular traps, and increased secretion of pro-inflammatory cytokines, including IL-6, IL-17A, and TNF-α. Additionally, aged neutrophils were associated with enhanced T- and B-cell activation. CXCR4 inhibition reduced aged neutrophil accumulation, alleviated inflammation, and restored intestinal barrier integrity by upregulating tight junction proteins (ZO-1, occludin). Collectively, these findings indicate that aged neutrophils may contribute to the pathogenesis of IBD by linking innate and adaptive immunity, amplifying inflammatory cascades, and promoting mucosal injury. Targeting these cells represents a promising therapeutic strategy for IBD.

Receptor-interacting protein kinase 2 (RIPK2): Structural insights, pathophysiological roles, and medicinal chemistry advances in inhibitor design.

Orchestrating mast cell for cancer immunotherapy.

Knockdown of histone deacetylase 9 ameliorates immunoglobulin a nephropathy by modulating immune response.

Latent tuberculosis infection (LTBI), characterized by the host immune system's ability to contain Mycobacterium tuberculosis (MTB) proliferation while failing to fully eliminate the pathogen, is a critical stage in tuberculosis prevention and control. Macrophages and alveolar epithelial cells together constitute the first line of defense. Following infection, MTB triggers a series of responses in which miRNAs, in concert with other biomolecules, coordinately regulate macrophage polarization, autophagic activity, the key metabolic pathways of autophagy, and the inflammatory response of host macrophages. This review summarizes the core mechanisms by which MTB exploits miRNAs to regulate host macrophage polarization, autophagy, and immunity, encompassing both the specific pathways that promote LTBI through autophagy inhibition and the induction of immunosuppressive phenotypes, and the shared mechanisms by which MTB disrupts host antimicrobial immunity during active tuberculosis.

Dual regulation of metabolism and immune contact by a self-reinforcing hydrogel enhances CAR-T-mediated residual tumor clearance and surveillance.

Targeting cutaneous inflammation: A review on advanced topical delivery systems and precision medicine in psoriasis.

From "Simulation" to "Mirror": Gene editing and humanization redefines the next-generation precision oncology animal model.

Engineering immune cells for next-generation therapies.

Memory CD8 T cells (TMEM) and exhausted CD8 T cells (TEX) are essential for host defense against infection and cancer, yet their therapeutic potential is often limited by insufficient persistence and sustained functional capacity. Strategies to enhance the longevity of both populations remain scarce. Here, we demonstrate that ablation of UBE2F, a neddylation E2 enzyme, induces a resilience program in CD8 T cells that operates across both TMEM and TEX compartments, resulting in improved viral and tumor control. This resilience state is characterized by enhanced self-renewal and survival without perturbing the conventional CD8 T cell differentiation trajectories. Mechanistically, UBE2F deficiency inhibited neddylation of CUL5, leading to accumulation of JUNB and upregulation of IL-2Rβ. The increased IL-2Rβ expression hypersensitizes CD8 T cells to physiological IL-15, thereby conferring the resilience features. Together, these findings identify the UBE2F-CUL5-JUNB-IL-2Rβ axis as a conserved posttranslational mechanism regulating CD8 T cell longevity across memory and exhausted states, providing a novel strategy for enhancing antiviral and antitumor immunity.

The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.

In the gut, the immune system is exposed to self and dietary antigens and antigens from microbes including potential pathogens. How the immune system distinguishes between this wide array of substances to mount appropriate responses that range from tolerance to immunity is not well understood. Accumulating evidence suggests that intestinal goblet cells may play a central role in the ability of the immune system to mount appropriate responses and to discriminate between innocuous substances and potential pathogens. Intestinal goblet cells can form goblet cell-associated antigen passages (GAPs), which acquire luminal substances and deliver them to the immune system. GAPs are closely regulated to not only control where and when antigen delivery to the immune system occurs but also to shape downstream immune outcomes. More recent studies suggest roles for GAPs in health and for GAP dysregulation as a contributor to disease. Here, we review emerging studies and concepts on the role of goblet cells and GAPs, highlighting implications of these observations on the pathogenesis of, and potential therapies for, disease.

Oncogenic gamma herpesviruses in humans, such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), can persist in the host for a long time by establishing persistent latent infection and by dynamic reshaping of the immune system that eventually can lead to virus-related malignancies. The focus of this narrative review is on the immune reprogramming of these viruses, which goes beyond mere immune evasion. Unlike immune escape, which is largely a passive process based on reduced antigen visibility or masking, immune reprogramming is an active and virus-directed remodelling of host immunity towards tolerance and tumour-supportive functions. Immune system rewiring, or functional rewiring, is essentially a multi-layered modulation of the innate and adaptive immune systems. By targeting similar and virus-specific pathways, these viruses can induce changes in the tumour microenvironment (TME) and alter the conditions in favour of their survival through the establishment and survival of tumour cells. Comparing the convergences and differences of the virus-specific consequences can help to understand how these viruses perform immune rewiring and highlight the challenges of therapeutic pathways and therapeutic resistance.

MAIT Cells in Tumor Contexts: Functional Diversity and Regulatory Hierarchies.

Macrophages are key regulators of cutaneous immunity, but the traditional M1/M2 polarization model cannot fully explain their functional diversity across skin diseases. In this narrative review, we use selected skin diseases to discuss a receptor-centered view of macrophage function and to illustrate a modular "receptor-pathway-effector" framework. This perspective places macrophage receptors at the upstream sensing level, where microbial products, tissue damage signals, cytokines, immune complexes, stromal cues, and tumor-derived signals are translated into inflammatory, reparative, fibrotic, or immunosuppressive programs. We summarize representative receptor modules, including pattern-recognition receptors, cytokine and chemokine receptors, Fc and complement receptors, scavenger and efferocytosis receptors, and inhibitory checkpoint receptors. Across psoriasis, atopic dermatitis, autoimmune blistering diseases, lupus, systemic sclerosis, sarcoidosis, leprosy, melanoma, cutaneous T-cell lymphoma, diabetic wounds, and radiation-induced skin injury, these modules help explain macrophage involvement in inflammation, remodeling, host defense, impaired repair, and tumor immune escape. We also discuss selected biomarker and therapeutic examples, while distinguishing clinically explored approaches from preclinical or emerging concepts. This receptor-centered perspective may complement existing views of macrophage heterogeneity and provide a clearer way to link receptor signals with disease-related macrophage functions.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed as a uniformly beneficial antiviral and antitumor signaling axis, emerging evidence reveals that cGAS-STING functions as a context-dependent immune rheostat whose impact is dictated by signal magnitude, timing, cellular origin, subcellular localization of signaling components, and tissue context. These parameters explain why pathway activation can promote tumor rejection, vaccine efficacy, and host defense in some settings yet drive immune suppression, metastasis, neuroinflammation, or autoinflammatory disease in others. In this Review, we synthesize mechanistic and clinical insights across agonist and antagonist strategies targeting the cGAS-STING pathway in cancer, infectious disease, neurodegeneration, and interferonopathies. We highlight why first-generation STING agonists have underperformed clinically and how next-generation delivery systems and cGAS-directed approaches may overcome these limitations. We propose a disease-centric framework that integrates spatial delivery, dosing architecture, and pharmacodynamic biomarker discovery to enable rational modulation of cGAS-STING, repositioning the pathway as a tunable immunologic control node for precision therapy rather than a binary on/off switch.

B cell development and longevity of IgE plasma cells.

The IL-36 cytokine family: From barrier immunity to therapeutic target in inflammatory diseases.

Temperature sensing shapes behavior and cellular functions, yet the molecular basis of thermosensitivity in non-neuronal cells remains poorly defined. Microglia are resident immune cells of the central nervous system that help maintain brain homeostasis via immune surveillance and injury responses. We previously showed that microglial motility is temperature dependent and is largely mediated by the thermosensitive ion channel transient receptor potential vanilloid 4 (TRPV4), a thermosensitive ion channel. However, the contribution of transient receptor potential melastatin 4 (TRPM4) is unclear because suitable Trpm4 mutant mice were not available in our earlier work. Here, we generated functional Trpm4-knockout mice (TRPM4KO) using CRISPR/Cas9 genome editing based on a published strategy. Time-lapse imaging of primary microglia across a range of temperatures revealed that Trpm4 deficiency did not alter temperature-dependent motility in vitro. These results indicate that TRPM4 is dispensable for temperature-dependent microglial motility.

Chronic viral hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) remains a leading global public health burden, driving progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) through complex interactions between viral replication, host immune responses, and extracellular matrix (ECM) remodelling. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that serve as central regulators of ECM homoeostasis and immune modulation in the liver. While physiological MMP activity is essential for tissue repair and immune surveillance, dysregulation of the MMP/TIMP (tissue inhibitors of metalloproteinases) axis during viral hepatitis promotes hepatic fibrogenesis, immune evasion, and malignant transformation, positioning MMPs as both drivers of disease progression and promising therapeutic targets. This review comprehensively examines the molecular and cellular mechanisms governing MMP/TIMP dysregulation across the spectrum of viral hepatitis, with particular focus on HCV and HBV. We address the reciprocal interactions between these viruses and MMP/TIMP expression, the roles of MMPs in liver fibrosis, viral replication, hepatocarcinogenesis, and immunomodulation of the tumour microenvironment, and the accelerated fibrogenic mechanisms in HIV-HCV and HIV-HBV coinfection. The review also extends to acute viral hepatitis (HAV and HEV), where direct MMP/TIMP data remain scarce but mechanistic and indirect ECM evidence indicate significant involvement. Finally, we critically evaluate current and emerging MMP-targeted therapeutic strategies including selective inhibitors, nanoparticle delivery systems, and RNA-based approaches and highlight key unresolved questions to guide future research towards disease-tailored interventions against viral hepatitis-driven liver damage and malignant progression.