We sought to determine whether the lymphatic vasculature functionally adapts to the organ in which it resides, such as along the gut. Duodenal lymphatic capillaries (lacteals) displayed the most discontinuous tight junction composition within the gut, resulting in a dependence on duodenal lacteals for rapid dietary lipid uptake. Duodenal helminths abrogated these features. Parallel RNA sequencing of lymphatic endothelial cells and mucosa along the intestine revealed that the transcriptomes overlapped in functional profiles. RNA sequencing also identified a putative VEGFR-2/3 signaling gradient that may explain differences in lacteal tight junctions along the small intestine at homeostasis. Transcriptionally, helminth infection triggered antimicrobial and angiogenic responses. While microbial depletion acted additively to helminths on lymphatic restructuring, glucocorticoids partially reversed helminth-induced lacteal changes. This suggests helminths induce lymphangiogenesis and associated lymphatic "zippering" via inflammation. Our study uncovers and explains the superior lipid absorption by duodenal lacteals and how it is compromised by helminths and provides transcriptional insights into lymphatic function along the gut.

The thymus exhibits constitutive activation of nearly all major inflammatory pathways, including sterile MyD88-dependent signaling and interferon production by mTECs, the presence of cellular and molecular components of type 1, type 2, and type 3 responses, as well as sustained B cell activation. The reasons for the existence of such a complex constitutively active inflammatory network at the site of T cell development-where the initial pathogen encounter is unlikely-have remained enigmatic. We propose that this inflammatory thymic 'ecosystem' has evolved to promote immunological tolerance to 'inflammatory self'-endogenous molecules absent from most peripheral tissues at steady state but upregulated during pathogen invasion. The spatial and temporal overlap with pathogen presence makes the discrimination of the inflammatory self from pathogen-derived molecules a unique challenge for the adaptive immune system. The frequent occurrence of diseases associated with autoantibodies against proinflammatory cytokines underscores the persistent risk of these molecules being misidentified as foreign. Their abundant representation in the thymus, therefore, is likely to be critical for maintaining tolerance. This review explores current insights into the thymic inflammatory network, its cellular and molecular constituents, and their role in the induction of T cell tolerance.

Macrophages exhibit remarkable functional plasticity by dynamically polarizing into proinflammatory or antiinflammatory subsets in response to microenvironmental cues. This duality underpins their pivotal roles in immune defense, tissue homeostasis, and disease progression; however, the molecular mechanisms governing their polarization and crosstalk across various pathologies remain incompletely defined. This review systematically delineates macrophage biology, emphasizing the interplay between subset-specific signaling networks and their context-dependent activation in both health and disease. The heterogeneity of macrophages is characterized by detailing the distinctions between tissue-resident and monocyte-derived origins, as well as their polarization states. Core pathways regulating phagocytosis, tissue repair, immune modulation, and neuroprotection are dissected, along with their dysregulation in autoimmune disorders, neurodegeneration, cancers, and cardiovascular diseases. Notably, microenvironmental factors such as damage-associated molecular patterns, pathogen-associated molecular patterns, and metabolic intermediates dynamically reshape macrophage phenotypes through NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation or signal transducer and activator of transcription (STAT)-mediated transcriptional control. Preclinical and clinical evidence underscores potential therapeutic targets and emerging strategies. The significance of this review lies in its integrative analysis of signaling crosstalk, paradoxical pathway roles, and translational implications for precision therapies. These insights into macrophage functions and signaling pathways provide a robust foundation for future disease intervention and personalized medicine.

Eosinophils are increasingly recognized as adaptable immune cells that exhibit diverse phenotypes and effector functions across different tissues and disease states. While they can induce pathology through degranulation and cytotoxic mediator release, eosinophils also fulfill regulatory and tissue repair roles. Advances in single-cell and spatial technologies have begun to reveal how microenvironmental cues (including cytokines, chemokines, and cell-cell interactions) shape eosinophil behavior in health and disease. These insights are critical for understanding why certain patients respond variably to therapies targeting eosinophils and related type 2 pathways. By dissecting eosinophil heterogeneity in real human tissues, researchers may identify new biomarkers, refine endotyping approaches, and develop more precise therapeutic strategies. This review summarizes emerging concepts of eosinophil biology in inflammatory conditions, highlights the impact of spatial context on eosinophil functions, and discusses the future of advanced phenotyping in guiding personalized treatments.

Biomaterial implants are a critical aspect of our medical therapies and biomedical research and come in various forms: stents, implantable glucose sensors, orthopedic implants, silicone implants, drug delivery systems, and tissue engineered scaffolds. Their implantation triggers a series of biological responses that often times lead to the foreign body response and subsequent fibrotic encapsulation, a dense ECM-rich capsule that isolates the biomaterial and renders it ineffective. These responses lead to the failure of biomaterials and is a major hurdle to overcome and in promoting their success. Much attention has been given to macrophage populations for the inflammatory component of these responses to biomaterials but recent work has identified an important role of T cells and their ability to modulate fibroblast activity and vice versa. In this review, we focus on T cell-fibroblast crosstalk by exploring T cell subsets, critical signaling pathways, and fibroblast populations that have been shown to dictate biomaterial-mediated fibrosis. We then highlight emerging technologies and model systems that enable new insights and avenues to T cell-fibroblast crosstalk that will improve biomaterial outcomes.

Cell-extracellular matrix (ECM) interactions play multiple roles in developmental, physiological, and pathological processes. ECM stiffness substantially affects cellular morphology, migration, and function. In this study, we investigated the effect of ECM comprising gelatin methacryloyl (GelMA) on the activation of rat basophilic leukemia (RBL-2H3) cells, a model mast cell line. Maintenance of intracellular Ca2+ concentration ([Ca2+]i) elevation and subsequent degranulation, evoked by crosslinking the high-affinity IgE receptors (FcεRI), were significantly suppressed in RBL-2H3 cells on collagen-coated GelMA hydrogel than those on collagen-coated glass dishes and plastic wells. Thapsigargin and phorbol myristate acetate caused sustained [Ca2+]i increase and degranulation to a similar extent in cells on both GelMA hydrogel and plastic wells/glass dishes. F-actin was clearly accumulated along the periphery of RBL-2H3 cells in plane attached to glass, but not GelMA hydrogel, suggesting that the loose actin cytoskeleton of RBL-2H3 cells on GelMA hydrogel caused suppressive degranulation through unstable FcεRI aggregation.

Type 2 inflammation and epithelial-to-mesenchymal transitions (EMTs) play critical roles in airway repair after damage from allergens or parasites. The matricellular protein periostin (POSTN) has increased expression in inflammatory conditions and has been implicated in fibrosis and EMT, suggesting a role in airway repair. This study investigates the role of periostin in airway epithelial and lung fibroblast wound repair using an in vitro wound model. Our results demonstrate that the type 2 cytokine IL-13 induces periostin secretion from primary human airway epithelial basal cells. Periostin knockdown in human airway epithelial cells (HAEs) and human lung fibroblasts (HLFs) impairs wound closure, indicating that periostin is required for airway repair. In a coculture model of HAE and HLFs, fibroblast-secreted POSTN is required for airway epithelial wound repair, suggesting that periostin is involved in paracrine signaling between the two cell types. These findings highlight periostin's critical function in epithelial and fibroblast-mediated wound repair, suggesting its potential as a therapeutic target for diseases characterized by aberrant wound healing and fibrosis, such as asthma and idiopathic pulmonary fibrosis.NEW & NOTEWORTHY This article highlights the critical role of periostin (POSTN) in airway epithelial and fibroblast-mediated wound repair. Moreover, the study reveals a paracrine signaling loop between airway epithelial basal cells and lung fibroblasts, emphasizing periostin's therapeutic potential for diseases like asthma and idiopathic pulmonary fibrosis.

Doublecortin-like kinase 1 (Dclk1) expression identifies cells that are rare in normal pancreas but occur with an increased frequency in pancreatic neoplasia. The identity of these cells has been a matter of debate. We employed Dclk1 reporter mouse models and single-cell RNA sequencing (scRNA-seq) to define Dclk1-expressing cells. In normal pancreas, Dclk1 identifies subsets of ductal, islet, and acinar cells. In pancreatic neoplasia, Dclk1 identifies several cell populations, among which acinar-to-ductal metaplasia (ADM)-like cells and tuft-like cells are predominant. These two populations play opposing roles, with Dclk1+ ADM-like cells sustaining and Dclk1+ tuft-like cells restraining tumor progression. The generation of Dclk1+ tuft-like cells requires the transcription factor SPIB and is sustained by a paracrine loop involving type 2 innate lymphoid cells (ILC2s) and cancer-associated fibroblasts (CAFs) that provide interleukin (IL)-13 and IL-33, respectively. Dclk1+ tuft-like cells release angiotensinogen to restrain tumor progression. Overall, our study defines pancreatic Dclk1+ cells and unveils a protective tuft cell-ILC2 axis against pancreatic neoplasia.

Memory T helper (Th) cells, generated in response to immunogenic challenges, are crucial in orchestrating adaptive immune responses. Acetylcholine (ACh), a key neurotransmitter of the parasympathetic nervous system, modulates immune function via muscarinic ACh receptors (mAChRs). This study investigates the role of mAChRs, particularly the M3 muscarinic ACh receptor (M3R), in regulating the cytokine and chemokine profile and NF-κB p65 activity in primary human memory Th cells. Memory Th cells were isolated from healthy donors and stimulated with anti-CD3/CD28/CD2 in the presence of oxotremorine-M (M1R-M5R agonist), atropine (M1R-M5R antagonist), or J104129 (M3R-selective antagonist). CHRM1-CHRM5 expression was quantified using RT-qPCR. M3R and phosphorylated NF-κB p65 were analyzed by Western blot. IFN-γ, IL-17A, and IL-4 were assessed by ELISA, while intracellular cytokine and chemokine receptor expression were measured by flow cytometry. CHRM3 knockout was performed using CRISPR-Cas9. Memory Th cells expressed all 5 mAChR subtypes. Oxotremorine-M increased IFN-γ and IL-17A while reducing IL-4 in an atropine-sensitive manner. Blocking or knocking out M3R prevented oxotremorine-M-induced increases in IFN-γ and IL-17A, but the suppression of IL-4 remained unchanged. Stimulation of mAChRs, particularly M3R, enhanced NF-κB p65 activity but did not affect chemokine receptor expression, cell proliferation, viability, or M3R levels. These findings indicate that mAChRs, including M3R, drive a pro-inflammatory memory Th-cell response through NF-κB p65 activation, while IL-4 suppression occurs independently of M3R. Targeting M3R specifically may provide a strategy for modulating adaptive immunity and treating inflammatory diseases.

Hydrogel-based three-dimensional (3D) co-culture systems are emerging as biomimetic platforms that more accurately recapitulate tissue architecture and microenvironmental interactions compared to conventional two-dimensional (2D) cultures. This study introduces an engineered 3D liver-like model to investigate compartment-specific responses to the potent hepatocarcinogen Diethylnitrosamine (DEN), with a focus on early events in carcinogenesis and tumor-stroma interactions. AML12 and 3T3 cell lines were treated with DEN or vehicle either in 2D culture or in 3D hydrogels in four experimental groups: (1) DEN-treated AML12 with vehicle-treated 3T3, (2) DEN-treated 3T3 with vehicle-treated AML12, (3) both cell types DEN-treated, and (4) both vehicle-treated. The cultured recombinants were subjected to proteomic profiling via mass spectrometry, followed by bioinformatics analysis and the results were validated through immunocytochemical staining (ICC). Gene ontology analysis revealed that cytoskeletal, RNA metabolism, and scaffold/adaptor proteins were among the most significantly enriched in 3D versus 2D models. Structural proteins emerged exclusively in mixed 3D co-cultures, reinforcing the organotypic nature of the system. Enriched pathways in 3D included intermediate filament organization, actin dynamics, and focal adhesion-pathways closely associated with liver carcinogenesis. Protein-protein interaction analysis demonstrated maximal network complexity in 3D cultures where both compartments were DEN-exposed. Survival analysis further identified poor-prognosis biomarkers (KRT20, KRT15, KRT14) uniquely enriched in this condition. ICC staining supported the proteomic findings. This organoid-like 3D co-culture model provides a physiologically relevant platform for investigating early-stage liver carcinogenesis and highlights the critical role of stromal-epithelial interactions. Its ability to replicate organ-level complexity and generate clinically relevant proteomic signatures supports its utility in translational cancer research and future drug discovery applications.

Pulmonary fibrosis results from persistent and pathological tissue repair, which is therapeutically challenging to attenuate and often fatal. The immune processes involved in fibrosis remain ill defined. Using a bleomycin-induced lung fibrosis murine model, we discovered that vagal TRPV1+ nociceptors are protective. Pharmacological ablation or genetic deletion of nociceptors resulted in worsened fibrosis and outcomes. Without nociceptors, alveolar macrophages aberrantly produced vasoactive intestinal peptide (VIP), leading to cytokine TGF-β1-mediated alternative proinflammatory Siglec-F+ neutrophil recruitment to the lung with a high propensity for neutrophil extracellular trap (NET) formation. VIP inhibition or Vip deletion in hematopoietic cells improved outcomes and attenuated Siglec-F+ neutrophil recruitment to the lungs in nociceptor-deficient mice, while VIP administration had the opposite effect. Thus, nociceptors are essential regulators of inflammation during pulmonary fibrosis. These findings provide mechanistic insights into how the nervous system impacts the progression of fibrotic lung diseases.

This study investigated the effect of Codium fragile (WCF) water extract in reducing allergic inflammation in ovalbumin (OVA)-induced mice. Mice were sensitized to OVA + aluminum hydroxide, administered WCF for one week, and exposed to 1% aerosolized OVA. As a result, WCF intake reduced the OVA-induced increase in CD4+ T cells, CD8+ T cells, the T helper type 2 (Th2)/T helper type 1 (Th1) cell ratio, and inflammatory cells such as eosinophils and lymphocytes. Furthermore, WCF reduced Th2 cytokines such as interleukin (IL)-5, IL-13, and IL-33 and inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IL-1β in lung tissues. A histological analysis showed that WCF intake decreases OVA-induced pulmonary inflammation, bronchial wall thickness, and mucus score and increases pulmonary alveolar area. Moreover, WCF inhibited the nuclear factor κB (NF-κB) pathway, the transforming growth factor β (TGF-β)/Smad pathway, and apoptosis-related proteins in lung tissues that OVA excessively activated. The oleamide (9-octadecenamide) content, representing a physiologically active component of WCF, was analyzed and validated using a high-performance liquid chromatography-photodiode array (HPLC-PDA) system. These results demonstrate that WCF may serve as a potential preventive agent for respiratory dysfunction such as allergic asthma by suppressing NF-κB and TGF-β/Smad pathways.

Fibrosis, characterized by abnormal deposition of structural proteins, is a major cause of tissue dysfunction in chronic diseases. The disease burden associated with progressive fibrosis is substantial, and currently approved drugs are unable to effectively reverse it. Immune cells are increasingly recognized as crucial regulators in the pathological process of fibrosis by releasing effector molecules, such as cytokines, chemokines, extracellular vesicles, metabolites, proteases, or intercellular contact. Therefore, targeting the immune microenvironment can be a potential strategy for fibrosis reduction and reversion. This review summarizes the recent advances in the understanding of the immune microenvironment in fibrosis including phenotypic and functional transformations of immune cells and the interaction of immune cells with other cells. The novel opportunities for the discovery and development of drugs for immune microenvironment remodeling and their associated challenges are also discussed.

The gut microbiota influences systemic immunity and the function of distal tissues, including the brain, liver, skin, lung, and muscle. However, the role of the gut microbiota in the foreign body response and fibrosis is largely unexplored. To investigate this connection, we perturbed the homeostasis of the murine gut microbiota via infection with the pathogenic bacterial species enterotoxigenic Bacteroides fragilis (ETBF) and implanted particulate material (mean particle size <600 μm) of the synthetic polymer polycaprolactone (PCL) into a distal muscle injury. ETBF infection in mice led to increased neutrophil and γδ T cell infiltration into the PCL implant site. ETBF infection alone promoted systemic inflammation, increased levels of neutrophils in lymphoid tissues, and altered skeletal muscle gene expression. At the PCL implant site, we found significant changes in the transcriptome of sorted stromal cells between infected and control mice, including differences related to ECM components such as proteoglycans and glycosaminoglycans. However, we did not observe ETBF-induced differences in fibrosis levels. These results demonstrate the ability of the gut microbiota to mediate long-distance effects such as immune and stromal responses to a distal biomaterial implant.

Innate lymphoid cells (ILC) distribution and compartmentalization in human lymphoid tissues are incompletely described. Through combined multiplex immunofluorescence, multispectral imaging, and advanced computer vision methods, we provide a map of ILCs at the whole-slide single-cell resolution level, and study their proximity to T helper (Th) cells. The results show that ILC2 predominates in thymic medulla; by contrast, immature Th cells prevail in the cortex. Unexpectedly, we find that Th2-like and Th17-like phenotypes appear before complete T cell receptor gene rearrangements in these immature thymocytes. In the periphery, ILC2 are more abundant in lymph nodes and tonsils, penetrating lymphoid follicles. NK cells are uncommon in lymphoid tissues but abundant in the spleen, whereas ILC1 and ILC3 predominate in the ileum and appendix. Under pathogenic conditions, a deep perturbation of both ILC and Th populations is seen in follicular lymphoma compared with non-neoplastic conditions. Lastly, all ILCs are preferentially in close proximity to their Th counterparts. In summary, our histopathology tool help present a spatial mapping of human ILCs and Th cells, in normal and neoplastic lymphoid tissues.

Observational studies have consistently reported positive associations between inflammatory biomarkers and the risk of developing aortic stenosis (AS). However, it is crucial to acknowledge that conventional observational studies are prone to various forms of bias, including reverse causation and residual confounding. To delve deeper into unraveling the potential causal relationship between inflammatory biomarkers and aortic stenosis, we conducted a comprehensive two-sample Mendelian randomization (MR) analysis.

In order to explore the causal effect of exposure to various circulating cytokines on the risk of developing AS, we carefully selected AS datasets as the exposures from the summary statistics of the genome-wide association study (GWAS) conducted by FinnGen. The dataset consisted of a sample size of 3283 for AS cases and 210,463 for controls. To estimate the MR analysis, we primarily adopted the inverse variance weighted (IVW) method. Additionally, we employed complementary methods, including Weighted Median, MR Egger, Weighted Mode, and Simple Mode, to analyze the causal associations comprehensively. In order to assess the presence of heterogeneity, we utilized Cochran's Q statistic and MR-Egger regression. To ensure the robustness and consistency of our findings, we conducted a leave-one-out analysis.

We observed a positive association between interleukin-18 (IL-18) levels and AS (odds ratio [OR] per standard deviation [SD] = 1.080; 95 % confidence interval [CI] 1.024 to 1.139), as well as between interferon-gamma levels (IFN-γ) and AS (OR per SD = 1.157; 95 % CI 1.028 to 1.302). Conversely, we found an inverse association between interleukin-13 (IL-13) levels and AS (OR per SD = 0.942; 95 % CI 0.890 to 0.997), as well as between interleukin-5 (IL-5) levels and AS (OR per SD = 0.892; 95 % CI 0.804 to 0.990).

Our research enhances the current understanding of the role of specific inflammatory biomarker pathways in aortic stenosis. Nevertheless, further validation is required to assess the viability of targeting these cytokines through pharmacological or lifestyle interventions as potential treatments for aortic stenosis.

Doxorubicin (DXR) is a widely used chemotherapy drug that can induce severe intestinal mucositis. Although the influence of gut bacteria on DXR-induced damage has been documented, the role of eukaryotic commensals remains unexplored. We discovered Tritrichomonas muris (Tmu) in one of our mouse colonies exhibiting abnormal tuft cell hyperplasia, prompting an investigation into its impact on DXR-induced intestinal injury. Mice from Tmu-colonized and Tmu-excluded facilities were injected with DXR. Tissue morphology and gene expression were evaluated at acute injury (6 h) and regenerative (72 h and 120 h) phases. Changes to crypt and villus morphology were more subtle than previously reported and region-specific, with significantly shorter jejunal villi in Tmu+ mice at 72 h post-DXR compared with Tmu- controls. Most notably, we observed elevated rates of DXR-induced apoptosis, measured by cleaved caspase 3 (CC3) staining, in Tmu+ intestinal crypts at 6 h post-DXR. Tmu+ mice also exhibited reduced expression of active intestinal stem cell (aISC) marker Lgr5 and facultative ISC (fISC) marker Ly6a at 6 h post-DXR compared with Tmu- controls. Tmu, but not DXR, was associated with increased inflammation and expression of type 2 cytokines IL-5 and IL-13. Tmu+ mice also exhibited a decreased fecal abundance of Lactobacillus, which promotes gut barrier integrity, and reduced claudin expression, indicating potential barrier dysfunction that could explain the increase in DXR-induced apoptosis. These findings highlight the significant influence of commensal microbiota, particularly eukaryotic organisms like Tmu, on intestinal biology and response to chemotherapy, underscoring the complexity of gut microbiota interactions in drug-induced mucositis.NEW & NOTEWORTHY Our study found that the eukaryotic commensal Tritrichomonas muris (Tmu) significantly increases DXR-induced intestinal apoptosis in mice. Tmu also reduces Lgr5 expression post-DXR injury and elevates inflammation and type 2 cytokine expression in the absence of injury. 16S sequencing identifies decreased abundance of protective Lactobacillus in Tmu colonized mice, as well as decreased expression of barrier-forming claudins, which may explain increased apoptosis. These findings emphasize the complex role of microbiota in drug-induced intestinal damage.

Metabolic syndrome is a cluster of some conditions such as high blood sugar, high blood triglycerides, low HDL cholesterol, abdominal obesity, and high blood pressure. Introducing a drug or a food that manages the majority of these medical conditions is invaluable. Tinospora cordifolia, known as guduchi and giloy, is a medicinal herb in ayurvedic medicine that is used in the treatment of various diseased conditions and also as a food for the maintenance of health. Here, we reviewed the current evidence supporting the role of giloy in the development and treatment of metabolic syndrome components. Appropriate articles that have been published until May 2024 were carefully extracted from PubMed, Scopus, and WOS databases to write a narrative review systematically. Gathered data showed the beneficial effects of giloy on metabolic syndrome components: hyperlipidemia, obesity, atherosclerosis, hypertension, and especially diabetes mellitus. As diabetes and insulin resistance seem to be a central feature of metabolic syndrome and in turn, can cause dyslipidemia, obesity, and, atherosclerosis, these beneficial effects are predictable with the anti-diabetogenic property of giloy. In this review, the main mechanisms of action of giloy in metabolic syndrome components are discussed. Based on the results, although giloy has been less investigated, considerable studies provide evidence of its beneficial effects on different components of metabolic syndrome. Relevant clinical trials are necessary to validate the mentioned effects, safety, and optimum dose of this herbal medicine and its components in managing different components of metabolic syndrome and transition from bench to bedside.

Hepatic fibrosis resulting from human mansonic schistosomiasis significantly impairs liver function and contributes substantially to morbidity associated with helminth infections. This pathological state develops following the deposition of helminth eggs within hepatic tissues, triggering a granulomatous inflammatory reaction. Schistosomiasis, a neglected tropical disease affecting approximately 240 million individuals globally, represents a major public health challenge. Although praziquantel (PZQ) is recommended by the World Health Organization (WHO) as the primary treatment for helminth infections, additional therapies are required to address the associated liver fibrosis. This study investigated the efficacy of tetramethylpyrazine (TMP), a natural compound known for its anti-inflammatory, antifibrotic, and hepatoprotective properties in various experimental models, in mitigating hepatic fibrosis induced by mansonic schistosomiasis. Our in vivo experiments demonstrated that TMP treatment significantly reduced hepatic granuloma size, as evidenced by histological analysis. Furthermore, our in vitro studies showed that TMP increased levels of the anti-inflammatory cytokine IL-10 while decreasing levels of the profibrotic cytokine IL-13 in a concentration-dependent manner. Immunofluorescence analysis also revealed that TMP effectively inhibited collagen deposition. Collectively, these findings suggest that TMP exhibits potential as an anti-inflammatory and antifibrotic agent for hepatic fibrosis resulting from Schistosoma mansoni infection.

The management of chronic rhinosinusitis with nasal polyps (CRSwNP) can be challenging, particularly when standard treatments including intranasal corticosteroids and endoscopic sinus surgery do not result in adequate symptom control. CRSwNP is frequently characterized by a type 2 immune signature, and many patients have other comorbid type 2 conditions, including asthma. There are currently 3 biologic therapies approved for the treatment of CRSwNP-omalizumab, mepolizumab, and dupilumab-and there are promising therapies in development. Biologic therapies allow for improved patient quality of life in CRSwNP, reduction in need for systemic corticosteroid treatment and endoscopic sinus surgery, and improvement in treatment of comorbidities. Translational studies assessing how biologic therapies can modify inflammation in CRSwNP have allowed for a greater understanding of CRSwNP pathogenesis. We review CRSwNP clinical trial and real-world data on the effectiveness and safety of biologics, discuss their therapeutic mechanisms, assess outcomes of biologic therapy versus endoscopic sinus surgery, and discuss therapies in development and future directions.

The intestinal mucosal immune system maintains homeostasis through complex interactions between epithelial cells and innate lymphoid cells in the lamina propria. Tuft cells, previously overlooked intestinal epithelial cell types, detect parasites and metabolites via Sucnr1 and TAS2R receptors. They secrete IL-25, which activates type 2 innate lymphoid cell (ILC2) via the IL-25R receptor. ILC2 releases IL-13, resulting in further promotion of tuft and goblet cells from stem cells. This positive feedback loop amplifies the local type 2 immune response, combating parasitic infections. Tuft cells also recognize viruses and bacteria, but the role played by the tuft cell-ILC2 circuit in this process is not yet clear. Furthermore, tuft cell-ILC2 circuit is influenced by dietary fiber, intestinal microbiota, and other factors, contributing to new functions in maintaining intestinal homeostasis. In inflammatory bowel disease, this immunological circuit may be protective. This review summarizes the current understanding of the tuft cell-ILC2 circuit, its regulatory mechanisms, and potential implications in intestinal disease.Graphical abstract (by Figdraw 2.0).

Cell therapy is a promising approach in regenerative medicine. However, maintaining the survival and function of injected or implanted therapeutic cells remains a substantial challenge to success. In vivo modulatory strategy for cell therapeutics has been recently developed, but suffers from limited regenerative efficacy in injured tissue microenvironment with chronic inflammation. Here, an off-the-shelf artificial macrophage (artM) assembled by M2 macrophages-derived lysate proteins-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres coated by macrophage cell membrane is developed. The synthetic artM fabricated in batches maintains its bioactivity with long-term cryostorage. Significantly, artM recapitulates the essential inflammation-regulatory and proregenerative characteristics of endogenous macrophages, including initiating M2 macrophage polarization, resolving excessive inflammation by releasing anti-inflammatory cytokines and growth factors, neutralizing endotoxins and proinflammatory cytokines, augmenting T-helper 2 (TH2) immune response, and coordinating cell migration and proliferation. In mouse model of deep tissue pressure injury (DTPI), the artM induces tissue regeneration by modulating the inflammatory microenvironment, promoting angiogenesis, reducing scar deposition, and accelerating the renewal of skin appendages. Depletion of macrophages in mice with skin ulcers highlights the immunomodulatory and proangiogenic functions of artM as effective as autogenous macrophages. Collectively, the engineered artM represents a cell-free, proreparative alternative to immune cell therapy in chronic wound management.

Wound healing (WH) poses a significant socio-economic burden due to its high incidence and recurrence rates. Iron overload (IO) could be a factor leading to delayed WH. This study thus analyzed IO-related genes (IORGs) in WH, offering possibilities for developing new therapeutic strategies. Differential gene expression (DEGs) analysis was conducted between the WH group and intact skin (IS) group, intersected with IORGs to obtain differentially expressed IORGs (DE-IORGs). Functional enrichment analysis and potential drug screening were performed on DE-IORGs. A protein-protein interaction (PPI) network of DE-IORGs was constructed, and hub genes were identified using CytoHubba and MCODE methods. ROC curves of hub genes were plotted, and their expression levels in WH and IS groups as well as inter-gene correlations were analyzed. Additionally, immune infiltration variances in WH and IS groups, along with miRNA and TFs of hub genes, were examined. Finally, the effect of EGFR on skin wound healing was verified by scratch healing assay. 39 DE-IORGs were predominantly enriched in signaling pathways like HIF-1 signaling pathway and Th17 cell differentiation. Potential drugs for treating WH (e.g., felbamate, SA-94315, GANT-58, rucaparib) were identified. Three hub genes related to IO in WH were pinpointed (HIF1A, CDKN2A, EGFR) with diagnostic value. Immune infiltration analysis showed higher levels of immune cells like endothelial cells and macrophages in the WH group. Additionally, 55 miRNAs (e.g., hsa-mir-200a-3p, hsa-mir-218-5p) and 2 TFs (L3MBTL2, ZNF76) regulating the three hub genes were predicted. Cell experiments showed that EGFR could promote skin wound healing. The study suggested HIF1A, CDKN2A, and EGFR as potential diagnostic biomarkers for effective WH diagnosis, offering new insights into identifying potenti1al therapeutic targets for WH treatment.

Chronic obstructive pulmonary disease (COPD) is characterized by immune dysregulation, including altered innate lymphoid cell (ILC) immune responses, particularly during exacerbations (ECOPD). Baicalin, a natural compound prevalent in various herbal medicines, has shown promise as a therapeutic candidate in ECOPD. However, its potential and molecular mechanism for addressing ILC immune imbalance during ECOPD remain poorly understood. First, this study conducted a cross-sectional analysis of ILC immune responses in stable COPD patients and those experiencing exacerbations. Then, clinical findings of skewed ILC immunity were validated in cigarette smoke and lipopolysaccharide-induced ECOPD mouse models. Lastly, the therapeutic effect of baicalin on restoring ILC immune homeostasis was investigated in experimental ECOPD mouse models. Significant downregulation of ILC2 immunity was observed during COPD exacerbations, accompanied by increased ILC1 and ILC3 responses, particularly in cases associated with bacterial infections. Notably, elevated IL-22 levels were observed in this group. Administration of recombinant IL-22 in ECOPD mouse models disrupted lung ILC homeostasis, specifically inhibiting the accumulation of ILC2. Proteomics and transcriptomics analyses suggested IL-22 as a mediator of type 2 immune suppression by creating a molecular environment that favors type 1 and type 3 immunity. Treatment with baicalin effectively restored ILC2 immunity by enhancing the recruitment and activation of lung ILC2 while suppressing ILC1 and ILC3 responses. Importantly, baicalin attenuated IL-22 production from lung ILC3, highlighting its potential as an IL-22 inhibitor. Baicalin demonstrates potential as a therapeutic strategy for addressing ILC immune imbalance in COPD exacerbations, particularly by restoring ILC2 immunity and partially inhibiting IL-22 production. Clinical registration The cross-sectional study was registered with the Chinese Clinical Trial Registry (ChiCTR2100050683).

Chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and post-surgical wound healing disorders pose a significant challenge due to prolonged healing, risk of infection, and impaired quality of life. Persistent inflammation and impaired tissue remodeling are common in these wounds. Traditional diagnostic methods, including visual inspection and microbiological cultures, offer limited insight into the wound micro-environment. Immunomarker profiling could provide a deeper understanding of the molecular mechanisms underpinning wound healing, offering potential biomarkers for infection status and healing progression.

This observational, multi-center cohort study, part of the 'Wound-BIOME' project, analyzed 110 swab samples from patients with acute and chronic wounds using multiplex immunoassays. Clinical parameters such as wound type, healing status, regeneration stage, and microbial burden were recorded. Total protein concentration was assessed, and 35 key immunomarkers, including cytokines (e.g. IL- 1α, IL- 1β), chemokines (CCL2, CXCL8, CXCL10), growth factors (FGF- 2, VEGF) and matrix metalloproteinases (MMP- 7, MMP- 9, MMP- 13), were quantified. Statistical analyses were performed to correlate immunomarker levels with clinical outcomes.

Pro-inflammatory markers, such as IL- 1β, IL- 18 and chemokines like CCL2 and CXCL8, were significantly elevated in non-healing and infected wounds compared to healing wounds. The study identified two new immunomarker ratios - IL- 1β/IL- 1RA and CXCL8/CXCL10 - as potential predictors of wound healing status. The IL- 1β/IL- 1RA ratio showed the highest accuracy for distinguishing healing from non-healing wounds (AUC = 0.6837), while the CXCL8/CXCL10 ratio was most effective in identifying infection (AUC = 0.7669).

Immunomarker profiling via wound swabbing offers valuable insights into the wound healing process. Elevated levels of pro-inflammatory cytokines and MMPs are associated with chronic inflammation and impaired healing. The IL- 1β/IL- 1RA and CXCL8/CXCL10 ratios emerge as promising biomarkers to distinguish between infection and inflammation, with potential in targeted wound care. Further studies are needed to validate these findings and implement them in clinical practice.

Innate lymphoid cells (ILC) have emerged as critical immune effectors with key roles in orchestrating the wider immune response. While ILC are relatively rare cells they are found enriched within discrete microenvironments, predominantly within barrier tissues. An emerging body of evidence implicates complex and multi-layered interactions between cell types, tissue structure and the external environment as key determinants of ILC function within these niches. In this review we will discuss the specific components that constitute ILC-associated microenvironments and consider how they act to determine health and disease. The development of holistic, integrated models of ILC function within complex tissue environments will inform new understanding of the contextual cues and mechanisms that determine the protective versus disease-causing roles of this immune cell family.

Trichinella spiralis (Ts) is known to cause cardiac fibrosis, which is a critical precursor to various heart diseases, and its progression is influenced by metabolic changes. However, the metabolic mechanisms remain unclear. Here, we observed that Ts-infected mice exhibited cardiac fibrosis along with elevated succinate levels in the heart using metabolomic analysis. Administration of succinate exacerbated fibrosis during Ts infection, while deficiency in succinate receptor 1 (Sucnr1) alleviated the condition, highlighting the role of the succinate-Sucnr1 axis in fibrosis development. Furthermore, metagenomics sequencing showed that Ts-infected mice had a higher abundance ratio of succinate-producing bacteria to succinate-consuming bacteria in the intestines. Notably, the succinate-producer Bacteroides vulgatus was enriched in Ts group. Oral supplementation with B. vulgatus aggravated Ts-induced cardiac fibrosis. In summary, our findings underscore the succinate-Sucnr1 axis as a critical pathway in helminth-induced cardiac fibrosis and highlight the potential of targeting this axis for therapeutic interventions. This study presents novel insights into the gut-heart axis, revealing innovative strategies for managing cardiovascular complications associated with helminth infections.

This review summarises some of the key features of interstitial lung diseases (ILDs) from a translational science point of view and brings insights into potential therapeutic options. Genetic predisposition and environmental factors like smoking, pollution and infections significantly impact the onset, progression and treatment response in ILDs, highlighting the need for personalised management. Fibroblasts are central to ILD pathology, influencing the tissue microenvironment, immune cell interactions and extracellular matrix (ECM) production, making them critical therapeutic targets. Monocyte-derived M2 macrophages drive fibrosis in idiopathic pulmonary fibrosis by secreting cytokines and remodelling the ECM. Understanding macrophage subtypes and their dynamics offers new therapeutic possibilities. Chronic type 2 immunity contributes to fibrosis, emphasising the need to enhance protective markers in order to even out the balance shift of pathological immune responses in ILD treatments. Serum biomarkers like Krebs von den Lungen-6 (KL-6), surfactant protein (SFTP) D, matrix metalloproteinase-7 (MMP-7), and C-C motif chemokine ligand (CCL)-18 are valuable for diagnosing and predicting ILD progression, although more research is needed for clinical application. Animal models, especially bleomycin-based models, offer insights into ILD pathology, but challenges like lung hyperinflation highlight the need for careful model selection and translational research to bridge preclinical and clinical findings.

In this study, a previously developed approach for creating a quantitative structure-activity relationship model anchored in an Adverse Outcome Pathway framework (AOP-anchored Nano-QSAR) is employed to develop a novel model capable of predicting transcriptomic responses triggered by the inhalation of multiwalled carbon nanotubes (MWCNTs). The acute phase response (AR) signaling pathway, which plays a crucial role in neutrophil influx and initiates the acute immune response is focused. This process involves recruiting pro-inflammatory cells into the lungs and can lead to lung fibrosis, as outlined in AOP33, or atherosclerosis, as per AOP237. To establish the relationship between the structural properties of a set of MWCNTs and the transcriptional benchmark dose level (BMDLAR) response of genes associated with the acute phase response signaling pathway, the locally weighted kernel linear regression algorithm is used. These findings emphasize the critical role of the aspect ratio and specific surface area of MWCNTs in initiating acute inflammation and, subsequently, lung pathologies and atherosclerosis through the inflammatory and acute phase response signaling pathways. This newly developed data-driven model extends the repertoire of transcriptomic-based, AOP-informed Nano-QSAR models, potentially serving as an in silico new approach methodology (NAM) to support the MWCNTs' safety assessment based on the weight of evidence.

Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.

Scar formation is characterized by dynamic alterations in collagen secretion, which critically determine scar morphology and pathological progression. In fibroblasts, collagen secretion is initiated through the activation of cytokine- and integrin-mediated signaling pathways, which promote collagen gene transcription. The procollagen polypeptide α chains undergo extensive post-translational modifications, including hydroxylation and glycosylation, within the endoplasmic reticulum (ER), followed by folding and assembly into triple-helical procollagen. Subsequent intracellular trafficking involves the sequential transport of procollagen through the ER, Golgi apparatus, and plasma membrane, accompanied by further structural refinements prior to extracellular secretion. Once secreted, procollagen is enzymatically processed to form mature collagen fibrils, which drive scar tissue remodeling. Recent advances in elucidating regulation of collagen secretion have identified pivotal molecular targets, such as transforming growth factor-beta 1 (TGF-β1), prolyl 4-hydroxylase (P4H), heat shock protein 47 (HSP47), and transport and Golgi organization protein 1 (TANGO1), providing novel therapeutic strategies to mitigate pathological scar hyperplasia and improve regenerative outcomes. This review provides a comprehensive analysis of the molecular mechanisms governing collagen secretion during scar formation, with emphasis on signaling cascades, procollagen biosynthesis, intracellular transport dynamics, and post-translational modifications, thereby offering a framework for developing targeted anti-scar therapies.

Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.

Respiratory syncytial virus (RSV) remains a significant global health concern, particularly for infants and young children in developing countries. Despite ongoing research efforts, an effective RSV vaccine has yet to be approved for widespread use. Use of two separate pattern recognition receptor (PRR) agonists as adjuvants in vaccine formulations has shown to enhance the immune response against the antigen. The limitation with the use of two adjuvants is that they need not necessarily bind to PRRs on the same cell. This study evaluates the efficacy of two different dual PRR binding chimeric molecules CL413 (TLR2/TLR7 agonist) and CL429 (TLR2/NOD2 agonist) as adjuvants for RSV virus-like particles (VLPs) delivered via the pulmonary route in mice for induction of mucosal and systemic immunity.

BALB/c mice were immunized twice with the RSV-VLPs alone or adjuvanted with CL413, CL429, mixture of single PRR agonists Pam3CSK4+ L18-MDP or Pam3CSK4+ imiquimod via the pulmonary route. The mixture of single PRR agonists adjuvants was used as control for chimeric adjuvants. Immune responses were evaluated by measuring antibody levels in sera and respiratory tract; cytokine production, B and T cell responses in the lungs and spleen.

Pulmonary immunization with CL413-adjuvanted VLPs induced robust nasal IgA responses against the RSV F and G proteins, which was not observed for the other adjuvant combinations. CL413 also enhanced serum IgG levels and promoted a balanced Th1/Th2 response, as evidenced by IgG2a/IgG1 ratios. CL413 elicited strong pro-inflammatory responses in the lungs of mice, including elevated levels of IFN-γ, TNF-α, IL-6, and IL-17A. Flow cytometry analysis revealed increased numbers of tissue-resident class-switched B cells in the lungs of mice that were immunized with VLPs adjuvanted with CL413 and CL429. CD4+ and CD8+ T cell responses were also enhanced in both lungs and spleens of mice receiving VLPs adjuvanted with chimeric molecules to various extents. Mice immunized with formalin inactivated RSV (FI-RSV), which are used as the positive control for vaccine induced pathology after RSV challenge developed alveolitis, perivascular infiltration. While all the mice receiving adjuvanted VLP formulations showed protection against lung pathology after RSV challenge.

The lack of pathology, combined with the robust mucosal and systemic immune responses, suggests that pulmonary delivery of adjuvanted RSV-VLPs may provide effective protection without the risk of vaccine-enhanced disease. The study also demonstrates that the chimeric TLR2/TLR7 agonist CL413 is a promising adjuvant for RSV-VLPs to induce mucosal and systemic immune response and warrant further investigations in more advanced preclinical models.

Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.

TNF-like cytokine 1A (TL1A) and its functional receptor, death-domain receptor 3 (DR3), are members of the TNF and TNFR superfamilies, respectively, with recognised roles in regulating innate and adaptive immune responses; additional existence of a decoy receptor, DcR3, indicates a tightly regulated cytokine system. The significance of TL1A:DR3 signalling in the pathogenesis of inflammatory bowel disease (IBD) is supported by several converging lines of evidence. Herein, we aim to provide a comprehensive understanding of what is currently known regarding the TL1A/DR3 system in the context of IBD. TL1A and DR3 are expressed by cellular subsets with important roles for the initiation and maintenance of intestinal inflammation, serving as potent universal costimulators of effector immune responses, indicating their participation in the pathogenesis of IBD. Recent evidence also supports a homoeostatic role for TL1A:DR3 via regulation of Tregs and innate lymphoid cells. TL1A and DR3 are also expressed by stromal cells and may contribute to inflammation-induced or inflammation-independent intestinal fibrogenesis. Finally, discovery of genetic polymorphisms with functional consequences may allow for patient stratification, including differential responses to TL1A-targeted therapeutics. In conclusion, TL1A:DR3 signalling plays a central and multifaceted role in the immunological pathways that underlie intestinal inflammation, such as that observed in IBD. Such evidence provides the foundation for developing pharmaceutical approaches targeting this ligand-receptor pair in IBD.

Lung type 2 immunity protects against pathogenic infection, but its dysregulation causes asthma. Although it has long been observed that symptoms of asthmatic patients often become exaggerated following food intake, the pathophysiological mechanism underlying this postprandial phenomenon is incompletely understood. Here, we report that lung type 2 immunity in mice is enhanced after feeding, which correlates with parasympathetic activation. Also, local parasympathetic innervations exhibit spatial engagement with such immune responses mediated by group 2 innate lymphoid cells (ILC2s). Pharmacologic or surgical blockage of parasympathetic signals diminishes lung type 2 immunity. Conversely, chemogenetic manipulation of parasympathetic inputs and their upstream neurocircuit is sufficient to modulate those immune responses. We then show that the cholinergic receptor muscarinic 4 (Chrm4) for the parasympathetic neurotransmitter acetylcholine is expressed in mouse or human lung ILC2s, and the Chrm4 deletion mitigates ILC2-mediated lung inflammation. These results have revealed a critical neuroimmune function of the gut-brain-lung reflex.