Adenomyosis is a common and difficult disease in gynecology. Its main clinical manifestations include uterine hypertrophy, excessive menstruation, pelvic pain and infertility, which have a serious impact on women’s health. Seriously affects women’s health. At present, the pathogenesis of this disease is not clear; however, the increase in local estrogen and the occurrence of an inflammatory response are widely believed to be closely related to the development of adenomyotic lesions. Although progress has been made in understanding how estrogen and inflammation play their respective roles in adenomyosis, the relationship between estrogen and inflammation and its impact on adenomyosis are not fully understood. In this work, we summarize the effects of estrogen and inflammation on the occurrence and development of adenomyosis, including the involved biological processes and related signal transduction mechanisms, as well as the targeted drugs for clinical treatment, and further summarize the interactions between the two in adenomyosis as well as the available evidence for clinical applications. This review helps to broaden our understanding of the role of the vicious inflammatory‒estrogen cycle in the pathogenesis and pathophysiology of adenomyosis, and it provides new ideas for the treatment of uterine adenomyosis. The vicious cycle of inflammation and estrogen promotes the development of adenomyosis.
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder with a complex pathophysiological mechanism and a marked sex difference in prevalence and disease severity, with women being more affected and showing a more aggressive disease course. Recent studies indicate that a complex interplay among gut microbiota (GM), their metabolites, and sex hormones is a crucial factor in AD pathogenesis. In this review, we attempted to synthesize current studies to critically discuss the tripartite interplay among GM, sex hormones, and the brain in AD. Firstly, we discuss the role of the microbiota-gut-brain axis in AD pathogenesis with a focus on how gut dysbiosis contributes to neuroinflammation, disruption of the blood–brain barrier (BBB), and accumulation of pathological proteins. Then, we discuss the mechanistic roles of various GM-derived metabolites in AD pathogenesis, with a focus on the two-edged role of SCFAs and their derivatives, the neuroactive role of tryptophan and its derivatives, and the modulatory roles of bile acids and trimethylamine N-oxide. Finally, we discuss a novel concept, the “microgenderome,” referring to the bidirectional interplay between sex hormones and GM, and how GM regulates sex hormone levels through unique enzymatic functions termed the “estrobolome” and a newly proposed “testobolome.”
This special issue features contributions from international experts, providing new perspectives on endometrial physiology and pathology: from regenerative mechanisms, epigenetic memory, immune checkpoints, and endocrine metabolic regulation to disease processes and therapeutic strategies.
The testis is an immune-privileged organ that balances protection of developing germ cells with the need to respond to pathogens. This review summarizes the dual nature of testicular immunity. A tolerogenic microenvironment is maintained through the blood-testis barrier (BTB) and immunomodulatory factors from Sertoli and Leydig cells, which suppress immune activation and preserve spermatogenesis. When infection, inflammation, or environmental stress disrupts this balance, immune responses shift toward pathology, inducing inflammatory cascades, apoptosis, and impaired fertility. We highlight the tightly regulated complement system, the plasticity and crosstalk of testicular immune cells—including macrophages, dendritic cells (DCs), T cells, and B cells—and the central role of the Toll-like receptor (TLR)-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome-Reactive oxygen species (ROS) axis in mediating inflammation and cell death. Viral infections further induce remodeling of the BTB, perturb immune homeostasis, and contribute to the development of orchitis. Overall, testicular immunity exhibits both protective and pathogenic features, offering insights for targeted therapies in male reproductive immune disorders. Testicular immunity balances immune privilege with context-dependent inflammatory activation. Sertoli, Leydig, and immune cells jointly regulate tolerance and drive pathology when disrupted. Viral and bacterial infections breach the BTB, alter immune homeostasis, and impair fertility.
Climate extremes are increasingly shaping both environmental and human health outcomes. Global warming has led to a rise in the frequency, duration, and intensity of extreme temperature events, with heatwaves emerging as one of the most hazardous weather-related threats. Beyond their well-recognized cardiovascular and respiratory effects, heat extremes are now understood to influence immune function. Growing evidence indicates that heat extremes along with air pollution, wildfires, humidity shifts, and ecosystem disruption can impair epithelial barrier integrity and disturb immune regulation. These stressors may promote chronic inflammation, alter adaptive immune responses, and compromise host defense mechanisms. Experimental and epidemiological data suggest that heat stress can reduce effective B-cell responses, modify antigen presentation, and increase inflammatory signaling, while combined exposures to heat and pollutants may further increase susceptibility to infectious, allergic, and autoimmune diseases. Although the physical drivers of climate change are well established, the biological pathways linking environmental stressors to immune dysregulation remain incompletely defined. This review synthesizes current evidence on the mechanisms by which extreme heat events influence immune tolerance and disease risk. We discuss implications for allergy, autoimmunity, and infectious diseases, highlight vulnerable populations, and outline key research priorities needed to inform clinical and public health adaptation.
The human microbiome has emerged as a critical modulator of cancer development, progression, and therapeutic response. Advances in sequencing and functional profiling have revealed that commensal microorganisms—particularly bacteria—interact closely with host immune and metabolic pathways, influencing tumor immunity across multiple cancer types. Dysbiosis of the gut microbiome has been associated with tumorigenesis, immune evasion, and resistance to therapy, while specific microbial taxa and metabolites have been shown to enhance antitumor immune responses. These discoveries have catalyzed the development of microbiome-based therapeutic strategies aimed at reshaping host–tumor interactions. This review summarizes current understanding of the cancer–microbiome axis, with a particular focus on therapeutic interventions that leverage microbial modulation. We discuss fecal microbiota transplantation (FMT) as an early, proof-of-concept approach demonstrating the capacity of the microbiome to restore responsiveness to immune checkpoint inhibitors, while also highlighting its limitations related to variability, standardization, and mechanistic uncertainty. We then examine emerging reductionist strategies, including supplementation with individual bacterial strains, defined consortia, and engineered microbes designed to deliver immunomodulatory payloads directly within the tumor microenvironment. Finally, we explore how microbial modulation interfaces with conventional cancer therapies such as chemotherapy, hormonal therapy, and cellular immunotherapies. Together, these studies illustrate a rapidly evolving field transitioning from correlative observations to mechanistically informed therapeutic design. While significant technical and biological challenges remain, continued integration of microbiology, immunology, and synthetic biology holds promise for translating microbiome-based interventions into safe, precise, and effective cancer therapies.
Sepsis is a life-threatening condition that is marked by dysregulated host immune responses that can induce multiorgan dysfunction. Recent evidence suggests that this immunopathology involves tissue-resident innate lymphocytes, including innate-lymphoid cells (ILCs) and innate-like lymphocytes (ILLs). This review elucidates the organ-specific roles of the three ILC groups (ILC1s, ILC2s, and ILC3s) and two ILL types (NKT and γδ T cells) in sepsis, particularly their cytokine-mediated functions and cell-cell interactions. The literature shows that in the lungs, ILC2-derived IL-9 and IL-13 mitigate pulmonary inflammation and preserve endothelial integrity but dysregulated ILC2 activation may exacerbate injury. In the heart, ILC2s may mediate cardioprotective effects by inducing IL-13-STAT3 signaling and IL-5-mediated eosinophil recruitment. Kidney-resident ILC2s may promote tissue repair in acute-kidney injury (AKI) but their role in sepsis-associated AKI remains underexplored. In the gut and liver, ILC3s protect from sepsis via IL-22, which promotes barrier integrity, but they can convert into ILC1s, whose IFN-γ contributes to tissue damage. Circulating NK cells may play pathogenic and beneficial roles at different times after sepsis onset. NKT and γδ T cells are respectively protective and pathogenic in the gut and liver, likely through their respective production of IFN-γ and IL-17 A. Thus, ILCs and ILLs play key roles in sepsis and could be potential therapeutic targets. Further research is needed to elucidate their precise contributions in each organ and how time since onset and local and systemic conditions affect these contributions.
Butyrate, a major microbial metabolite derived from dietary fiber fermentation, has emerged as a key regulator in the pathogenesis and treatment of asthma. It modulates the functions of dendritic cells, macrophages, and T cells, thereby reshaping the inflammatory microenvironment. In parallel, butyrate influences the transcriptional activity of inflammation-related genes through epigenetic mechanisms such as histone acetylation, DNA demethylation, and miRNA regulation. Notably, butyrate mediates long-range immune modulation via the gut-lung axis, linking intestinal microbial homeostasis to pulmonary inflammation. This review summarizes current advances in understanding the central role of butyrate within the immune-epigenetic-gut-lung network and discusses emerging therapeutic strategies based on microbiota modulation and targeted delivery systems. Regulation of the butyrate pathway offers new insights into the complex pathogenesis of asthma and potential avenues for innovative therapeutic development.
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract (GI tract). Despite extensive research, its exact pathogenesis remains elusive. However, multiple factors are thought to be involved in the onset and progression of IBD. Aside from genetic risk factors, microbial dysbiosis, environmental cues, defects in the epithelial barrier, as well as a dysregulated intestinal immune response, are critical players driving a vicious cycle, which ultimately results in chronic disease. An orchestrated interaction between the intestinal microbiota and the immune response, especially TH17 cells, is critical for maintaining and re-establishing intestinal homeostasis. Nonetheless, a misguided interaction contributes to the pathogenesis of IBD. Indeed, depending on the microenvironment, intestinal TH17 cells possess dual properties. Either they act to control the inflammatory response, or they acquire pro-inflammatory features promoting the development of intestinal pathology. This context-dependent phenotype of TH17 cells has recently been associated with the microbiota composition, which shapes the inflammatory milieu of the gut. To establish precision immunomodulation as a therapeutic strategy for patients with IBD, it is critical to understand how intestinal microorganisms are involved in actively directing the dichotomous nature of TH17 cells and their cytokine products.
First described by Joseph Paneth in 1888 in the small intestine, particularly in the crypts of Lieberkühn, Paneth cells have since emerged as a critical subtype of intestinal epithelial cells (IECs), which together constitute the body’s largest interface with the external environment, continuously exposed to pathogens, dietary components, and toxins. Paneth cells represent a unique, long-lived secretory IEC population located at the crypt base, where they play indispensable roles in antimicrobial defense and stem cell niche maintenance. Their differentiation, positioning, and survival are governed by tightly regulated signaling networks, including the Wnt and Notch pathway. Although traditionally viewed as terminally differentiated, emerging evidence suggests Paneth cells possess a certain level of plasticity, enabling functional adaptation or dedifferentiation under stress or injury. These characteristics position Paneth cells as central regulators of intestinal homeostasis and epithelial barrier integrity. Over the last decades, accumulating evidence has established that Paneth cell dysfunction is closely linked to microbial dysbiosis and the development of inflammatory bowel disease (IBD), highlighting their contribution to disease pathogenesis. Recent discoveries on how Paneth cell dysfunction contributes to intestinal inflammation are uncovering new therapeutic approaches aimed at reestablishing Paneth cell homeostasis and alleviating IBD progression. In this review, we comprehensively summarize current knowledge on Paneth cell differentiation, function, and their role in gut host defense and epithelial barrier maintenance. We further discuss mechanisms by which Paneth cell dysfunction disrupts intestinal homeostasis, promoting IBD development, and highlight emerging therapeutic strategies that target Paneth cells to reestablish barrier integrity and restore gut health.
Inflammatory bowel disease (IBD) is a multifactorial and heterogeneous disorder that remains challenging to manage. Growing evidence implicates the gut microbiome as a key player in IBD pathogenesis, with many patients displaying intestinal dysbiosis that can drive aberrant immune responses. Traditional microbiome-targeted interventions, such as dietary modifications, probiotics, and fecal microbiota transplantation (FMT), have yielded mixed and often temporary benefits in IBD. This shortcoming of broad-spectrum approaches underscores the need for more precise, personalized strategies that account for each patient’s unique microbiota and disease phenotype. Recent advances in omics and bioengineering have catalyzed the development of emerging microbiome-directed therapies that move beyond these broad approaches. This narrative review highlights emerging microbiome-directed therapies that aim to restore gut homeostasis and mitigate inflammation in IBD. We critically evaluate the rationale and therapeutic potential of rationally designed bacterial consortia and genetically engineered bacteria, which represent next-generation probiotics tailored to complement deficient microbial functions or deliver anti-inflammatory agents in situ. We also expand the discussion to underexplored microbiome constituents – archaea, protists, bacteriophages, and fungi – highlighting their roles in IBD and potential as therapeutic targets. Finally, we discuss the key advances and ongoing challenges of these innovative approaches, from ecological stability and engraftment to safety and regulatory considerations.
Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants; nonetheless, besides supportive measures, no treatment is available. NEC significantly increases length of hospitalization of preterm infants, causes severe morbidity and up to 70
Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by a triad of pathogenic mechanisms, including: a) microvascular hyperreactivity secondary to endothelial dysfunction, b) dysregulated immune activation of both innate and adaptive immunity, with the production of autoantibodies targeting nuclear antigens (e.g., anticentromere antibodies, anti-RNA polymerase III antibodies, and anti-topoisomerase I antibodies), and c) fibrosis of the skin and internal organs, such as the lungs, due to excessive extracellular matrix deposits produced by dysregulated myofibroblasts. Skin involvement plays a crucial role in the detrimental impact of SSc on quality of life. Skin fibrosis in SSc is characterized by the progressive accumulation of extracellular matrix components, including collagen, in the dermis, and is associated with adipocyte atrophy in the hypodermis. Visceral manifestations include fibrotic interstitial lung disease (ILD), myocardial involvement, pulmonary arterial hypertension, gastrointestinal manifestations, and scleroderma renal crisis. These manifestations are key determinants of prognosis and significant contributors to mortality in SSc. This review will explore the clinical features of SSc, the existing subtypes based on different classification approaches (such as skin-driven classifications, autoantibodies, or molecular subsets), epidemiology, identified etiologies, pathogenesis, current standards of care, and a selection of potential therapeutic perspectives. This review will emphasize SSc-related skin manifestations, including their pathogenesis and treatment, while also discussing other organ manifestations.
Pyoderma gangrenosum (PG) is a rare inflammatory skin disease belonging to the group of neutrophilic dermatoses. The pathogenesis of PG involves a predisposing genetic background that facilitates a dysregulated innate and adaptive immune response, with an imbalance between pro-inflammatory and anti-inflammatory mediators, leading to neutrophil-driven inflammatory damage. Several immunosuppressants and immunomodulatory drugs are currently available for the treatment of PG, in combination with topical therapies, wound management and pain control strategies. Systemic corticosteroids and cyclosporine remain the first-line treatment options with the best evidence. However, in recent years, the rise of knowledge about different pathogenic mechanisms has led to a significant increase in studies attesting the efficacy and safety of biologic therapies including, among others, antagonists of tumour necrosis factor (TNF)-α and interleukin (IL)-23, becoming the drug of choice in specific clinical setting. Similarly, different small molecules such as JAK-STAT (Janus kinase/signal transducer and activator of transcription) inhibitors are showing promising results for the treatment of PG. We review established and emerging pathogenesis-driven treatments, also providing a therapeutic algorithm and informing future directions in the management of PG.
Conventional dendritic cells (cDCs) play a pivotal role in orchestrating the delicate balance between immunity and tolerance within the gastrointestinal tract by interacting with other cell types, particularly T cells. Meanwhile, the microbiota is critical for the induction and modulation of the immune system in the gut and plays a key role in the function of cDCs. So far, the study of intestinal cDCs has been encumbered by their limited numbers and phenotypic overlap with other myeloid cells. Recent advancements in single-cell sequencing technology have helped define cDCs and their subsets, while also providing valuable insights into the contribution of cDCs to Inflammatory Bowel Disease (IBD). However, the exact role of cDCs in IBD remains unclear, particularly in terms of how the microbiota influences their function in this context. In this review, we summarize the functions of cDCs in the intestine and during IBD, and the role of the microbiota in cDC biology. We also describe the current limitations in the study of cDCs and the microbiota, as well as new methods for studying DC-T cell communications in vivo, which can help increase our understanding of the function of cDCs in the intestine and develop new therapeutic strategies against IBD.
Uterine disorders, such as thin endometrium and intrauterine adhesions, remain significant challenges in reproductive medicine, often leading to infertility and poor pregnancy outcomes. Recent advances in regenerative medicine and tissue engineering have led to the development of innovative therapeutic strategies aimed at restoring endometrial structure and function. Biomaterials play a central role in these advancements, serving not only as structural scaffolds and delivery vehicles for stem/progenitor cells and bioactive molecules but also as modulators of the tissue microenvironment by promoting angiogenesis and regulating immune responses. Mesenchymal stem cells from various sources, including female reproductive tissues, along with their extracellular vesicles, have demonstrated potential in promoting angiogenesis, reducing fibrosis, and modulating immune responses for endometrial repair. Additionally, platelet-rich plasma and a range of pharmacological agents—often with advanced drug delivery systems, such as nanocarriers—further contribute to endometrial regeneration. Engineered scaffolds, particularly those derived from decellularized extracellular matrix or fabricated using three-dimensional bioprinting technologies, closely mimic the biomechanical and biochemical properties of native endometrium. These scaffolds facilitate cellular engraftment and provide valuable platforms for in vitro modeling of endometrial physiology. The development of uterus-derived extracellular matrix scaffolds with immunologically compatible biomaterials and organoids marks a pivotal step toward reducing immune rejection and improving clinical applicability. This review highlights recent progress in biomaterial-based therapeutics for uterine regeneration and discusses the remaining challenges in shifting therapeutic paradigms of personalized and tissue-specific regenerative strategies.
Galectins, a family of β-galactoside-binding proteins, are critical in regulating feto-maternal interactions during pregnancy. Their evolutionary trajectory is reflected in their expression patterns and diverse functions in embryo implantation, trophoblast invasion, and maternal immune and vascular adaptation, contributing to healthy placentation and uncomplicated pregnancy. Galectin-1 (gal-1), one of the most ancient galectins, plays a pivotal role in feto-maternal immune regulation, acting predominantly from the maternal side to promote immune tolerance, a function integrated early in placental mammalian evolution. In contrast, anthropoid primates introduced a unique set of fetal (placental) galectins (gal-13, gal-14, and gal-16) through birth-and-death evolution, with these genes localized on human chromosome 19. Notably, these primate species have evolved varying degrees of deep placentation, with humans exhibiting the deepest, which facilitates enhanced nutrient delivery to the fetus, particularly for brain development. Placental galectins have been implicated in the evolution of immune tolerance mechanisms that support deep placentation. During pregnancy, reduced expression of maternal galectins (e.g., gal-1) and placental galectins (e.g., gal-13) has been associated with severe obstetric complications, signaling disruptions in feto-maternal tolerance. This review provides a comprehensive overview of gal-1, gal-13, gal-14, and gal-16, highlighting their shared and unique roles in maternal and placental immune regulation and placental development. Additionally, the review explores the potential of maternal versus placental galectins as biomarkers and therapeutic targets to improve diagnostic and treatment strategies for adverse pregnancy outcomes.
Anaphylaxis is a severe, potentially life-threatening allergic reaction that can occur through both IgE- and non-IgE-mediated pathways. The classic IgE-mediated pathway involves allergen-specific IgE binding to FcεRI on mast cells and basophils, triggering degranulation and the release of inflammatory mediators. Non-IgE-mediated mechanisms, which are commonly associated with drug-induced reactions, at least in mice, involve the activation of the G-protein-coupled receptor (MRGPRX2), triggering mast cell degranulation in an IgE independent manner. Anaphylaxis can also be mediated through IgG immune complex interaction with Fc gamma receptors on various cell types, leading to mediator release. This review will describe current understanding of the pathomechanisms of anaphylaxis. Understanding these diverse pathways is crucial for accurate diagnosis, effective treatment, and prevention of anaphylaxis.
Dermatomyositis (DM) is an infrequently encountered idiopathic inflammatory myopathy distinguished by distinctive cutaneous manifestations and/or progressive muscle weakness. This review provides an updated exploration of DM, emphasizing cutaneous features, etiopathogenesis, and therapeutic implications. DM presents a heterogeneous spectrum, ranging from classic forms involving both skin and muscle to clinically amyopathic DM, which lacks significant muscle involvement but carries risks like interstitial lung disease (ILD) and malignancy. Recent advances in understanding DM pathogenesis underscore the roles of myositis-specific autoantibodies, type I interferons, and cytokine dysregulation in disease activity and clinical outcomes. Specific antibodies such as anti-Mi-2, anti-TIF1γ, and anti-MDA5 define subtypes of DM, aiding diagnosis, prognosis, and tailored management strategies. While conventional immunosuppressive therapies like glucocorticoids and antimalarials form the cornerstone of treatment, many cases remain refractory, particularly involving chronic skin disease. Emerging targeted therapies, including Janus kinase inhibitors and monoclonal antibodies, show promise in addressing type I interferon-driven pathways and refractory symptoms. Future research aims to refine diagnostic criteria, integrate biomarkers, utilize more robust outcome measures, and develop targeted therapeutics to improve outcomes while minimizing treatment-related toxicity. This review consolidates current knowledge and highlights the need for a multidisciplinary, individualized approach to managing DM, focusing on both established and novel treatment avenues.
