Background: Ponatinib (PON), an effective tyrosine kinase inhibitor for leukemias harboring the T315I mutation, is limited by severe cardiotoxicity, including myocardial infarction and heart failure. Here, we investigated the therapeutic potential of Bone Morphogenetic Protein-7 (BMP-7), an anti-inflammatory growth factor, in a murine model of PON-induced cardiotoxicity. Methods: C57BL/6J mice were distributed into experimental groups receiving PON (25 mg/kg cumulative dose) either alone or with BMP-7 (600 μg/kg cumulative dose), along with a corresponding control group. Cardiac analyses included molecular and histological assessments. Results: PON administration induced a marked increase in monocyte infiltration and M1 macrophage polarization. These inflammatory events led to the upregulation of the pyroptotic cascade, leading to activation of the TGF-β1/SMAD2/3 signaling axis. In contrast, BMP-7 significantly attenuated these pathological responses by suppressing inflammation-induced pyroptosis and the TGF-β1/SMAD2/3 signaling axis. Conclusions: These findings identify inflammation-induced pyroptosis as a central driver of the pathological changes in PON-induced cardiotoxicity. Notably, our work highlights BMP-7’s capacity to inhibit these disease-related alterations. Collectively, these results expand on the current knowledge of the mechanistic framework of PON-induced cardiotoxicity, while also emphasizing BMP-7 as a promising therapeutic candidate with potential translational relevance.

Not available.

Traumatic brain injury triggers a complex immune response that plays a dual role in central nervous system recovery and neuroinflammation. Among various immune regulators, CD44-a cell surface adhesion molecule-has been implicated in traumatic brain injury pathology, but its precise functional role remains to be elucidated. In the present study, we demonstrated that CD44 expression is upregulated in the meninges following traumatic brain injury and that it plays a central role in orchestrating monocyte recruitment and activation within this compartment. Using a controlled cortical impact mouse model, we combined transcriptomic profiling with flow cytometry, western blotting, and immunohistochemistry analyses to identify a distinct immune signature characterized by increased meningeal monocyte infiltration and exacerbated neuroinflammation. Genetic knockdown of CD44 markedly altered this trajectory: it reduced monocyte-mediated inflammation, suppressed neuronal apoptosis, and significantly improved behavioral recovery. These findings identify CD44 as a critical mediator linking meningeal immune cell dynamics to post-traumatic neuroinflammatory processes. Thus, targeting CD44 may be a promising therapeutic strategy to modulate immune surveillance and promote neural repair following traumatic brain injury.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, and there is currently a lack of early rapid identification and effective treatment methods. During the pathogenesis of sepsis, immune cells such as monocytes exhibit abnormal activation of aerobic glycolysis. However, the mechanism of glycolysis in immune cells during sepsis remains to be elucidated. Here, we investigated the role of glycolysis-related regulatory genes in the development of sepsis. Through analysis of the GEO database, we found that HK3 is significantly elevated in the peripheral blood of sepsis patients. Receiver operating characteristic (ROC) curve analysis demonstrated that HK3, as a novel metabolic checkpoint, serves as an excellent diagnostic biomarker for sepsis. Immune cell infiltration analysis revealed a significant increase in monocyte infiltration in the peripheral blood of sepsis patients. Single-cell RNA sequencing analysis demonstrateda significant increase in HK3 expression in monocytes from the sepsis group compared to the control group. Using an LPS-induced monocyte sepsis model, we found that HK3 boosts glycolytic activity and lactate accumulation. Mechanistically, this enhances inflammatory cytokine secretion through H3K18 lactylation-dependent activation of IL-6 and TNF-α genes. Notably, targetedHK3knockdown effectively suppressed this pro-inflammatory cascade, highlighting its critical role in sepsis pathogenesis. Our findings not only establishHK3as a key metabolic regulator in sepsis but also elucidate its molecular mechanism in driving excessive monocyte-mediated inflammation. Moreover, we identifyHK3as a promising therapeutic target for mitigating hyperinflammatory responses in sepsis.

Remote ischemic postconditioning (RIC) has emerged as a novel promising intervention to reduce damage after stroke. However, the mechanisms underlying the beneficial effect of RIC are unclear. The recent study using ischemic stroke in mice model found that RIC enhances the infiltration of pro-inflammatory monocytes to the damaged brain and that these monocyte-derived macrophages have improved phagocytic capacity, allowing for the efficient brain cleanup. They subsequently discovered that scavenger receptor CD36 act as central molecule involved in monocyte infiltration and in macrophages phagocytic activities. Ultimately, they found that the cleanup is essential to prevent axonal degeneration and substantial nigra degeneration.

New-onset refractory status epilepticus (NORSE) is a devastating neurological condition characterized by the sudden onset of prolonged, drug-resistant seizures in previously healthy individuals. A clinically relevant animal model is essential to elucidate its pathophysiology, improve treatment, and reduce morbidity and mortality in NORSE. We developed an adolescent mouse model of NORSE by inducing prolonged convulsive status epilepticus in postnatal day 40 (P40) C57BL/6 J mice-corresponding to human adolescence-via unilateral intrahippocampal kainic acid (IHKA, 150 ng) injection. Progression of recurrent spontaneous electrographic seizures was monitored through depth electrodes on days 3, 5, 7, and 21 post-IHKA. Cellular and immune responses were examined using immunohistochemistry, Nissl staining, and flow cytometry. Behavioral outcomes were assessed using open-field and Y-maze tests. IHKA-injected mice developed spontaneous recurrent seizures by day 3 (18.7 ± 3.2 seizures/hour). Seizure frequency nearly doubled by day 7 (35.2 ± 4.1 seizures/hour) and continued through day 21 (39.7 ± 4.8 seizures/hour). Significant neuroinflammatory changes were observed, including > 9-fold microglia activation, two-fold astrocytosis, cell death in the CA3 subfields, and monocyte infiltration into the hilus. Flow cytometry revealed a two-fold increase in CD8+ cytotoxic T cells and γδ T cells in the hippocampus. Behaviorally, IHKA mice exhibited increased anxiety and cognitive deficits by day 21. This adolescent IHKA model recapitulates hallmark features of NORSE-acute repetitive convulsive seizures with rapid progression to subclinical status epilepticus, marked immune activation, hippocampal injury, and behavioral impairment. Our murine model of NORSE provides a valuable platform for investigating NORSE pathogenesis and evaluating novel therapeutic strategies.

Platelet Endothelial Cell Adhesion Molecule-Dependent Leukocyte Transmigration Is an Essential Early Event in Endotoxin-Induced Uveitis.

Localized scleroderma (LSc) is an autoimmune condition characterized by localized cutaneous sclerosis, sometimes extending into deeper tissues. Phototherapy, including excimer laser therapy (ELT), is considered an effective and minimally invasive treatment option for patients without extracutaneous involvement. However, little is known about the histopathological and molecular alterations that occur during treatment. Here, we report a case of circumscribed morphea successfully treated with ELT, accompanied by detailed longitudinal histological analysis. A 78-year-old woman presented with gradually progressive indurated plaques on both sides of the abdomen. Histopathological examination of the lesional skin revealed dense collagen deposition and perivascular infiltration of lymphocytes, monocytes, and mast cells, confirming the diagnosis of circumscribed morphea. Topical glucocorticoid therapy yielded insufficient improvement, prompting the addition of 308-nm ELT. The patient underwent 12 ELT sessions, administered every two to four weeks with incremental dosing from 100 mJ/cm2 to 240 mJ/cm2, reaching a cumulative dose of 2100 mJ/cm2. This regimen resulted in marked clinical improvement within one year. Post-treatment biopsies demonstrated near-complete resolution of dermal sclerosis, with substantial reductions in inflammatory cell infiltration. Toluidine blue staining and immunohistochemistry further revealed dynamic cellular changes: mast cells and CD3+ T cells were significantly decreased; CD34 expression, absent in lesional dermal mesenchymal cells before treatment, was restored; and α-smooth muscle actin-positive myofibroblasts, abundant at baseline, were markedly reduced following ELT. These findings indicate that ELT not only ameliorates clinical sclerosis but also reverses immune and mesenchymal cell alterations associated with fibrosis. This case highlights the therapeutic potential of ELT in circumscribed morphea and suggests a plausible mechanism by which ELT modulates immune-mesenchymal interactions to attenuate fibrosis in LSc.

Matrix metalloproteinase 9 (MMP9) is a zinc-dependent endopeptidase involved in extracellular matrix (ECM) remodeling and inflammatory signaling. Although MMP9 has been implicated in tumor progression and immune modulation in solid tumors, its clinical relevance and microenvironmental associations in diffuse large B-cell lymphoma (DLBCL) remain incompletely defined. Publicly available transcriptomic and clinical datasets of DLBCL were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE56315). Differential expression and enrichment analyses were performed to characterize biological pathways associated with MMP9 expression. Immune and stromal features were estimated using CIBERSORT, TIMER, and ESTIMATE algorithms. Associations with tumor stemness indices and somatic mutational profiles were explored. In addition, peripheral blood leukocyte profiles were analyzed from an independent cohort of DLBCL patients collected at our institution to assess systemic immune alterations associated with disease status. MMP9 protein expression was further evaluated using immunohistochemical data from the Human Protein Atlas. MMP9 expression was significantly elevated in DLBCL tissues compared with normal lymphoid controls. Higher MMP9 expression was associated with inferior overall survival and increased immune and stromal scores. MMP9 expression correlated with enhanced monocyte and myeloid cell infiltration and enrichment of ECM-related and cytokine-associated signaling pathways, including PI3K-Akt signaling. Analysis of peripheral blood samples revealed altered leukocyte distributions in DLBCL patients, characterized by increased neutrophil and monocyte proportions and reduced lymphocyte fractions, particularly in cases with bone marrow involvement. In addition, MMP9-high tumors exhibited distinct mutational patterns involving genes such as KMT2D and MYD88, along with reduced tumor stemness indices. Immunohistochemical analysis confirmed increased MMP9 protein expression in DLBCL tissues. Elevated MMP9 expression is associated with adverse prognosis and immune-stromal alterations in DLBCL. Integrated transcriptomic, genomic, and clinically derived peripheral blood analyses suggest that MMP9 expression reflects ECM-associated immune remodeling at both local and systemic levels, supporting its potential value as a biomarker linked to the tumor immune microenvironment in lymphoma.

Construction and validation of golgi apparatus-related genes as predictors of the immune microenvironment and prognosis in colorectal cancer.

Mycobacterium tuberculosis (Mtb) remains a significant public health threat, responsible for 1.6 million deaths in 2021. The development of new treatments is particularly urgent for immunocompromised individuals, including those with Mtb/HIV coinfection, who experience severe disease outcomes. Previous studies demonstrated that blockade of VEGFR1, a receptor expressed on monocytes that mediates their recruitment to infection sites, limits Mtb-induced pathology in immunocompetent mice of both Mtb-resistant (C57BL/6J) and Mtb-susceptible (B6.C3H-sst1) strains. The present study extends these findings by evaluating the VEGFR1/2 blockade strategy in immunocompromised hosts. Treatment with the VEGFR1/2 blocker SU5416 (semaxanib) reduced monocyte infiltration into the lungs of Mtb-infected immunocompromised RAG1KO mice without affecting bacterial protection. Reduced monocyte recruitment improved lung pathology. VEGFR1/2 blockade also decreased the number of NK cells in the lungs of RAG1KO mice. Notably, an elevated ratio and increased absolute number of neutrophil granulocytes were observed in the Mtb-infected lungs of both immunocompetent and immunocompromised mice following SU5416 administration. However, this increase in neutrophils did not exacerbate lung pathology, as most recruited granulocytes remained within the lung vasculature. The beneficial effect of VEGFR1/2 blockade in RAG1KO animals suggests that further investigation of VEGFR blockers, such as SU5416, as adjunctive therapy to anti-tuberculosis drug regimens for immunocompromised populations with tuberculosis is warranted.

Modeling immune cell recruitment within a wound-relevant microenvironment remains challenging. Here, we developed a novel skin-derived extracellular matrix (ECM) hydrogel model to study monocyte (THP-1) entry and phenotypic changes within a dermal fibroblast-populated (NHDF) matrix. The main novelty of this study is that it compares the effects of fibroblast-derived soluble signals and active monocyte infiltration in a 3D biomimetic model. Signaling by fibroblast-secreted soluble factors enhanced a pro-angiogenic secretome (e.g., >3-fold upregulation of VEGFA at day 1) and promoted endothelial tube formation (increasing network junctions to 1.16 ± 0.16 vs. 0.93 ± 0.23 in monoculture). In contrast, this paracrine signaling did not induce the matrix-driven pro-fibrotic response in hydrogels. Crucially, physical immune infiltration restricted monocyte penetration (mean depth of 8.92 ± 2.27 μm vs. 121.1 ± 15.9 μm in monoculture at day 5), reduced hydrogel-induced myofibroblast activation (decreasing α-SMA+ cells from 79.1% to 54.3% upon initial contact), and was associated with slower collagen loss during the early phase. (retaining a high-density collagen ratio of 3.46 ± 0.33 vs. 2.02 ± 0.29 in monoculture at day 1). These observations were accompanied by a shift toward a matrix-stabilizing profile, including increased TIMP expression and reduced pro-fibrotic markers. (ACTA2 and COL1A1). By including active immune infiltration (which was absent in previous tSVF models), we capture the transition from inflammation to the proliferation stage. Although the later stages of extensive ECM remodeling appear suppressed here, they may occur as repair progresses. Overall, our findings highlight that the immune cell is a key regulatory component for coordinating matrix preservation and vascular support. Importantly, this model replicates the early phases of wound healing, a stage where the monocyte-fibroblast secretome supports endothelial network formation. We established this innovative 3D ECM hydrogel system as a practical and physiologically relevant platform to investigate immune-matrix-stromal crosstalk.

In the current scenario, safe and efficacious drugs for the therapy of pulmonary fibrosis have been extremely rare. Moreover, the oral dosage forms available in the market offer limited therapeutic efficacy with numerous side effects. Hence, pulmonary fibrosis is untreatable to date. Quercetin dihydrate (QD) is a traditional medicine reported to have mast cell-stabilizing, anti-fibrotic, and anti-inflammatory properties for the treatment of pulmonary fibrosis. QD has poor bioavailability; hence, a nanosuspension (NS) was developed to enable efficient pulmonary delivery. QD-NS through inhalation therapy is a novel targeted drug delivery for the therapy of pulmonary fibrosis. To overcome the limitations of oral dosage forms, we have developed an inhalation therapy of quercetin dihydrate nanosuspension (QD-NS) through a top-down approach. The NS was optimized by adjusting factors like stabilizer, pressure, and cycle of high-pressure homogenizer (HPH). The quality and stability of the optimized formulation were evaluated through in vitro and stability studies, whereas the efficacy of the formulation was determined with in vivo studies. The % fine particle fraction was obtained as 69.07 ± 0.135% thereby indicating aerosol drug deposition into the lower region of the lungs. The value for MMAD and GSD was recorded as 0.28µm and 2.30µm, respectively, which indicates drug targeting into the lungs with a narrow distribution of particles with uniform particle size. The drug release profile of QD-NS expresses sustained release of the drug, and the formulation was most stable at storage conditions of 2-8°C. In pharmacodynamic studies, the QD-NS (inhalation group) exhibited significant decreased levels of transforming growth factor β (TGF-β) (p < 0.01 and p < 0.001), lactate dehydrogenase (LDH) (p < 0.001 and p < 0.01), and alkaline phosphatase (ALP) (p < 0.01 and p < 0.0001) in both preventive and treatment aspects, compared with the silica-induced diseased group. Moreover, it also reduced the inflammatory cell infiltration of lymphocytes (p < 0.01 and p < 0.0001), granulocytes (p < 0.01 and p < 0.0001), monocytes (p < 0.01 and p < 0.0001), monocytes (p < 0.01 and p < 0.0001), and WBC (p < 0.0001 and p < 0.0001) in the lungs for co- and post-treatment. Additionally, on comparing QD-NS (inhalation group) with QD-NS (oral group), the inhalation therapy showed better efficacy due to its targeted action. The data reveal that QD-NS inhalation therapy offers improved efficacy with enhanced bioavailability for the treatment of pulmonary fibrosis.

Chronic kidney disease (CKD) is characterized not only by progressive fibrosis but also by systemic endothelial dysfunction and inflammation. Platelets, traditionally recognized for their role in hemostasis, also serve as key modulators of endothelial activation and immune cell recruitment. Platelet activation is commonly observed in patients with CKD and contributes to the proinflammatory environment. Although platelet-endothelial interactions are well-characterized in cardiovascular disease, their role in renal endothelial dysfunction and inflammation remains poorly understood. To investigate this, we used the unilateral ureteral obstruction (UUO) model in mice, to examine how platelet activation influences endothelial responses and monocyte/macrophage recruitment in the early phase of renal fibrosis development. Platelet depletion reduced the number of infiltrating macrophages in kidney tissue, decreased expression of endothelial activation and inflammation markers, and preserved the peritubular capillary (PTC) integrity. Further in vitro studies using human umbilical vein endothelial cells (HUVECs) showed that activated platelets induced endothelial dysfunction and inflammation, in line with the in vivo findings. To recapitulate the vascular microenvironment, we performed a shear flow-based transmigration assay. Monocyte adhesion and transendothelial migration significantly increased when endothelial cells were pretreated with activated platelets compared to unstimulated controls. Moreover, the presence of platelets on the inflamed endothelium further enhanced monocyte migration, suggesting a synergistic effect in promoting immune cell recruitment. Collectively, our findings highlight that activated platelets contribute to endothelial dysfunction, inflammation, and monocyte infiltration in early kidney injury, suggesting their potential as a therapeutic target to mitigate microvascular injury and preserve renal vascular integrity in kidney disease.

BackgroundHead and neck squamous cell carcinoma (HNSC) is a highly heterogeneous malignancy with poor prognosis and frequent recurrence. Beyond tumor-intrinsic alterations, the immune microenvironment plays a decisive role in tumor initiation and progression. However, the causal contribution of systemic plasma proteins to immune regulation and HNSC susceptibility remains poorly defined.MethodsWe conducted a multi-sample Mendelian randomization (MR) study integrating large-scale plasma proteomics, immune cell phenotypes, and HNSC. Mediation analyses were performed to identify immune cell phenotypes that potentially mediate protein-HNSC associations. The findings were further supported by immune infiltration analyses, molecular docking and molecular dynamics simulations and validation using clinical HNSC specimens, including single-cell RNA sequencing of collected samples, scTenifoldKnk virtual knockout modeling and immunofluorescence staining/histological assessment of HNSC tissues.ResultsAmong 4907 plasma proteins, MR identified prefoldin subunit 2 (PFDN2) as a protective factor against hypopharyngeal carcinoma, with no evidence of reverse causality. Immune phenotype MR analyses revealed CD64 on monocyte (FCGR1A+ monocytes) as the only immune trait causally linked to both PFDN2 and cancer risk. Analysis using multiple deconvolution algorithms demonstrated a consistent negative correlation between PFDN2 expression and monocyte infiltration. Single-cell RNA sequencing revealed predominant PFDN2 expression in epithelial tumor cells, whereas FCGR1A expression was restricted to monocytes. Virtual knockout of PFDN2 selectively activated monocyte-associated inflammatory programs. Molecular docking and dynamics simulations supported a stable protein-protein interaction between PFDN2 and CD64. Tissue analyses further confirmed PFDN2 downregulation and CD64 upregulation in HNSC, correlating with advanced tumor grade and stage.ConclusionsOur findings establish PFDN2 as a protective plasma protein that restrains HNSC progression by suppressing CD64 on monocyte-mediated inflammatory immune microenvironments, highlighting the PFDN2-CD64 axis as a potential prognostic biomarker and therapeutic target.

BackgroundIdiopathic membranous nephropathy (IMN) is an antibody-mediated glomerulopathy in which podocyte-directed autoimmunity is well characterized, whereas the immunometabolic programs of innate immune cells within the renal microenvironment remain poorly defined. Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1, encoded by INPP5D) is a key negative regulator of PI3K signaling in myeloid cells and an emerging immunopharmacologic target, but its role in IMN is unknown.MethodsBulk and single-cell RNA-seq analyses were performed using public human IMN datasets, and the passive Heymann nephritis (PHN) rat model was used specifically for in vivo validation of key histopathological and signaling readouts to dissect INPP5D/SHIP1-centered immunometabolic pathways in IMN. Public glomerular transcriptomes from IMN and control kidneys were deconvoluted using CIBERSORT and ESTIMATE to quantify immune/stromal components and infer infiltrating leukocyte subsets. Differentially expressed genes were intersected with curated immune- and metabolism-related gene sets to identify immunometabolic hubs. Single-cell RNA-sequencing datasets were used to localize INPP5D and related pathways to specific renal cell populations, reconstruct monocyte differentiation trajectories and metabolic states, and infer ligand–receptor communication with podocytes. Key findings were validated in PHN rats by assessing proteinuria, renal histopathology, immune cell markers, podocyte proteins and SHIP1-related signaling molecules.ResultsIMN kidneys exhibited elevated immune and stromal scores, with increased infiltration of monocytes and naïve B cells and a relative depletion of regulatory T cells. Cross-differential analyses identified five overlapping immune–metabolic genes (INPP5D, PLCG1, KL, ACO1, ARG2), among which INPP5D was significantly upregulated and predominantly expressed in monocytes. Single-cell analyses revealed that renal monocytes in IMN displayed enhanced steroid biosynthesis, a skewed trajectory toward an M1-like state and strengthened SPP1-mediated communication with podocytes. In PHN rats, we recapitulated key clinical and histological features of IMN, accompanied by increased monocyte/macrophage infiltration, altered podocyte markers, and upregulation of SHIP1 and downstream PI3K/Akt signaling.ConclusionsThese data delineate an INPP5D/SHIP1-centered immunometabolic program in renal monocytes as a potential regulatory factor of pathological monocyte–podocyte crosstalk in IMN. Targeting SHIP1-related PI3K/Akt pathways and monocyte immunometabolism may offer novel immunomodulatory strategies for risk stratification and disease modification in membranous nephropathy.

BackgroundAcute-on-chronic liver failure is a fatal syndrome involving sudden hepatic deterioration in patients with chronic liver disease, resulting in high short-term mortality. The intrahepatic molecular mechanisms that drive disease progression are poorly understood, partly due to limited access to human liver tissues.MethodTranscriptomic profiling of liver tissues from patients with hepatitis B virus-related acute-on-chronic liver failure and a corresponding murine model was performed. Comparative analyses were conducted across disease stages to delineate the dynamic immune and metabolic trajectories.ResultThe analysis uncovered a conserved immune-metabolic dysregulation during disease progression. In both patients and mice, immune activation-characterized by monocyte and macrophage infiltration and altered cytokine signaling-coincided with progressive metabolic failure, including the suppression of mitochondrial functions. The murine model further demonstrated a transition from an early stage of hyperinflammation to a later stage of immune exhaustion. Moreover, several monocyte and macrophage-associated genes were identified as conserved markers that correlate with disease severity, highlighting their potential as biomarkers or therapeutic targets.ConclusionThis study defines a conserved immune-metabolic interplay during the progression of hepatitis B virus-related acute-on-chronic liver failure and validates the murine model’s accuracy for studying the disease’s terminal stage. The identified dysregulation of immune cells and metabolic pathways presents actionable targets for developing stage-specific therapies intended to disrupt the disease’s vicious immune-metabolic cycle.

Deciphering the molecular consequences of protein cleavage in inflammatory signaling is vital for defining the mechanisms of intestinal autoinflammation and identifying new therapeutic targets for inflammatory bowel disease (IBD). While it was previously established that HOIL-1 cleavage by MALT1 negatively regulates NF-κB activation and inflammatory responses in vitro, the pathophysiological role of HOIL-1 cleavage in regulating intestinal inflammation and the specific function of the resulting C-terminal fragment (C-HOIL-1) remained elusive. This study aimed to define the role of HOIL-1 cleavage and C-HOIL-1 in modulating gut inflammation. To investigate the impact of HOIL-1 cleavage on intestinal inflammation, the global and myeloid-specific transgenic mouse models with uncleavable HOIL-1 (lacking C-HOIL-1) were established, and their disease phenotypes and immune profiles were characterized under DSS-induced colitis. Genetically engineered THP-1 monocytic cells expressing uncleavable HOIL-1 and C-HOIL-1 were constructed to elucidate the molecular mechanisms of C-HOIL-1 in regulating inflammatory signaling. Finally, Lenti-C-HOIL-1 was delivered to the colon of wild-type mice via enema to evaluate the therapeutic potential of C-HOIL-1 in controlling intestinal inflammation. Mice with uncleavable HOIL-1 (lacking C-HOIL-1) present a more severe disease phenotype in DSS-induced colitis; specifically, the infiltration of inflammatory monocytes, M1-type macrophages, and neutrophils is significantly elevated in the colon. Mechanistically, we discover that C-HOIL-1 has novel biological functions in i) inhibiting NF-κB signaling, ii) interacting with STAT1 to down-regulate STAT1-mediated inflammatory signaling, and iii) up-regulating ARG1 expression. Collectively, these actions suppress the inflammatory responses in monocytes/macrophages, and impede the differentiation of M1-type macrophages. The pretreatment of Lenti-C-HOIL-1 to the colon of wild-type mice alleviates DSS-induced intestinal inflammation. Our results define the pathophysiological role of HOIL-1 cleavage in colitis, and unveil new functions of C-HOIL-1 in regulating myeloid inflammatory responses. These findings provide a potential therapeutic strategy for controlling gut inflammation in IBD.

In vitro models can recapitulate aspects of human liver diseases, thereby aiding therapeutic development. Dynamic interactions with vascular and immune cells contribute to disease progression in ways that are challenging to capture in the hepatic spheroid models commonly used for assessing facets of metabolism and disease. To address this, we developed a microphysiological system (MPS) featuring multicellular human hepatic spheroids physically integrated with self-organized microvascular networks. We demonstrate this MPS’s utility by modeling an insulin resistance state, where chronic exposure to disease-mimetic conditions yields altered hepatocyte metabolism, dysregulated vascular features, and increased inflammation state. We extend this system to capture disease-relevant changes in immune cell recruitment, showing that monocytes perfused through the vasculature will extravasate toward hepatic spheroids, with insulin-resistant samples exhibiting greater infiltration. Altogether, this vascularized liver MPS captures local hepatocyte-immune-microvascular interactions in an accessible microfluidic platform, enabling the study of clinically relevant immune-tissue interactions in complex metabolic disease.

Collagen galactosyltransferase 1 (COLGALT1), a key enzyme involved in collagen post-translational modification, has been implicated in extracellular matrix remodeling across multiple cancer types, yet its prognostic significance and relationship with the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC) remain unclear. In this study, we analyzed multi-omics datasets from public repositories to assess COLGALT1 expression patterns, clinical relevance, and prognostic value in ccRCC. Quantitative real-time PCR was performed to validate its expression in renal cancer cell lines and normal renal tubular epithelial cells. Immune infiltration profiles were characterized using multiple computational algorithms, and a competing endogenous RNA network was constructed to explore regulatory mechanisms. Our results demonstrated that COLGALT1 expression was significantly upregulated in ccRCC at both mRNA and protein levels and was positively associated with the infiltration of monocytes, T helper 2 cells, macrophages, regulatory T cells, and natural killer cells. Notably, COLGALT1 expression correlated strongly with markers of M2 macrophages, suggesting a role in promoting an immunosuppressive tumor microenvironment. These findings identify COLGALT1 as a novel prognostic biomarker and potential therapeutic target in ccRCC, highlighting its contribution to extracellular matrix remodeling and immune regulation.