Mouse Model Research Articles

Targeting TRPC channels for control of arthritis-induced bone erosion

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca 2+ -selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels. While ELP-004 minimally affected physiological RANKL-induced osteoclast maturation in murine bone marrow– and spleen-derived myeloid cells (BMSMCs) and human PBMC-derived cells, it potently interfered with osteoclast maturation driven by TNFα or LTB4. The contribution of TRPC channels to osteoclastogenesis was examined using BMSMCs derived from TRPC4 −/− or TRPC(1–7) −/− mice, again revealing preferential interference with osteoclastogenesis driven by proinflammatory cytokines. ELP-004 also reduced bone erosion in a mouse model of rheumatoid arthritis. These investigations reveal TRPC channels as critical mediators of inflammatory bone erosion and provide insight into the major target of ELP-004, a drug currently in preclinical testing as a therapeutic for inflammatory arthritis.

Characterization of Cutaneous Radiation Syndrome in a Mouse Model Using [18F]F- Fluorodeoxyglucose Positron Emission Tomography

Abstract Ionizing radiation on the skin has the potential to cause various sequelae affecting quality of life and even leading to death due to multi-system failure. The development of radiation dermatitis is attributed to oxidative damage to the skin’s basal layer and alterations in immune response, leading to inflammation. Past studies have shown that [18F]F-2-fluoro-2-deoxyglucose positron emission tomography-computed tomography ([18F]F-FDG PET/CT) can be used effectively for the detection of inflammatory activity, especially in conditions like hidradenitis suppurativa, psoriasis, and early atherosclerosis. Since currently there are no specific tests for radiation dermatitis, our study aimed to validate whether radiation dermatitis induced in mice can be accurately visualized and measured using [18F]F-FDG PET/CT. We induced cutaneous radiation syndrome in BALB/c mice with different radiation absorbed doses and monitored symptom development through photography, PET imaging, and histopathology, marking the first attempt at non-invasively quantifying radiation dermatitis effects at the molecular level using PET imaging. Our results showed that there were progressive changes in the dorsal skin of irradiated mice, with notable differences between those exposed to varying doses of radiation. Erythema, epilation, and desquamation were more pronounced in mice exposed to lower doses (25 Gy and 35 Gy) than at 45 Gy; however, by the third week, severe skin deterioration, including ulceration and dermal atrophy, was evident in mice irradiated with 35 Gy and 45 Gy. PET/CT imaging revealed increased [18F]F-FDG uptake in the irradiated dorsal skin area of all mice compared to controls, with more pronounced avidity for the lesion in the 25 Gy and 35 Gy than the 45 Gy. Comparison of tissue-normalized SUVMax values showed that both the 25 Gy and 35 Gy mice exhibited fourfold [18F]F-FDG uptake in the dorsal skin compared to controls, while a twofold uptake was seen at 45 Gy, thus indicating substantial metabolic changes in the dorsal skin induced by radiation exposure. Histopathological analyses correlated with the above findings, demonstrating generalized hypertrophy and epidermal thickening in all irradiated mice compared to controls, with thicker epidermis observed with higher radiation doses and increased destruction of microvasculature. In conclusion, PET/CT emerges as a successful tool for imaging cutaneous radiation syndrome, with the observed dermal changes in irradiated mice closely aligning with metabolic alterations of the affected area.

Spatiotemporal landscape of kidney in a mouse model of hyperuricemia at single‐cell level

AbstractSerum uric acid is an end‐product of purine metabolism. Uric acid concentrations in excess of the physiological range may lead to diseases such as gout, cardiovascular disease, and kidney injury. The kidney includes a variety of cell types with specialized functions such as fluid and electrolyte homeostasis, detoxification, and endocrine functions. Two‐thirds of uric acid is excreted through kidney, however, the exploration of markers and new therapeutic targets in renal tissue of hyperuricemia is still lacking. Single‐cell and spatial omics techniques represent major milestones in life sciences. The combined measurement of the physical structure and molecular characteristics of tissues facilitates the exploration of the pathophysiological processes underlying disease development and the discovery of possible therapeutic targets. Here, the spatiotemporal atlas of hyperuricemic nephropathy was investigated using single‐cell RNA sequencing, spatial transcriptomics, spatial proteomics, and spatial metabolomics in a urate oxidase knockout mouse model. Several emerging targets and pathways especially ribosome and metabolism related to uric acid excretion were discovered and will be investigated further in studies on lowering uric acid.

Artemisia herba-alba Essential Oil: Chemical Composition, Phytotoxic Activity and Environmental Safety

Weeds cause a decrease in the quantity and quality of agricultural production and economic damage to producers. The prolonged use of synthetic pesticides causes problems of environmental pollution, the possible alteration of agricultural products and problems for human health. For this reason, the scientific community’s search for products of natural origin, which are biodegradable, safe for human health and can act as valid alternatives to traditional herbicides, is growing. Essential oils can have useful implications in agriculture by acting as effective alternatives to chemical herbicides. In this work, the chemical composition of an EO from Artemisia herba-alba and its herbicidal properties were studied on two weeds (Lolium multiflorum and Trifolium pratense) and two crops (Brassica napus and Hordeum vulgare) and its environmental safety was also assessed using three model organisms: Chaoborus sp., Tubifex tubifex and Eisenia foetida. The principal component of the EO was camphor (26.02%), with α- and β-thujone (9.60 and 8.38%, respectively), 1,8-cineole (8.02%), piperitenone (5.29%) and camphene (4.95%) as the main components. The EO demonstrated variable phytotoxic effects with a dose-dependent manner, inhibiting both the germination and the radical elongation of the tested seeds, and was also found to be environmentally safe for the selected organisms. The results lay the foundation for considering this EO as a potential weed control agent.

Effects of Cirsium japonicum var. maackii on avelliation of metabolic disease by improving insulin resistance

BackgroundMetabolic syndrome (MetS) refers to a group of risk factors that cause health problems, such as obesity, diabetes, dyslipidemia, and hyperglycemia. MetS is characterized by insulin resistance, which leads to abnormal insulin sensitivity. Cirsium japonicum var. maackii (CJ) is perennial herbaceous species found in Asia that exhibits antioxidant, antidiabetic, antitumor, antifungal, and anti-inflammatory activities. In this study, we aimed to measure the effects of CJ on MetS by improving insulin resistance in a db/db type 2 diabetes mouse model. After administrating CJ extract (CJE) for db/db mouse for 6 weeks, we measured with the evaluation of Insulin resistance, lipid profiles, histological analysis of liver, damage of liver and kideny.ResultsThe results showed that CJE was effective in reducing body weight and fat mas and showed a positive effect on lowering blood glucose and improving insulin sensitivity. CJE improved dyslipidemia by increasing serum-HDL levels and decreasing serum-LDL levels. In addition, CJE reduced liver and kidney damage in histological analysis.ConclusionsThese results demonstrate the anti-diabetic effects of CJE and suggest its potential for improving MetS. Therefore, CJE may have potential values as a functional food material for managing MetS.

Regulation of Fibroblast Phenotype in Osteoarthritis Using CDKN1A-Loaded Copper Sulfide Nanoparticles Delivered by Mesenchymal Stem Cells

This study aimed to investigate the regulation of fibroblast phenotypes by MSCs delivering copper sulfide (CuS) nanoparticles (NPs) loaded with CDKN1A plasmids and their role in cartilage repair during osteoarthritis (OA). Single-cell RNA sequencing data from the GEO database were analyzed to identify subpopulations within the OA immune microenvironment. Quality control, filtering, PCA dimensionality reduction, and tSNE clustering were performed to obtain detailed cell subtypes. Pseudotime analysis was used to understand the developmental trajectory of fibroblasts, and GO/KEGG enrichment analyses highlighted biological processes related to fibroblast function. Transcriptomic data and WGCNA identified CDKN1A as a key regulatory gene. A biomimetic CuS@CDKN1A nanosystem was constructed and loaded into MSCs to create MSCs@CuS@CDKN1A. The characterization of this system confirmed its efficient cellular uptake by fibroblasts. In vitro experiments demonstrated that MSCs@CuS@CDKN1A significantly modulated fibroblast phenotypes and improved the structure, proliferation, reduced apoptosis, and enhanced migration of IL-1β-stimulated chondrocytes. In vivo, an OA mouse model was treated with intra-articular injections of MSCs@CuS@CDKN1A. Micro-CT scans revealed a significant reduction in osteophyte formation and improved joint space compared to control groups. Histological analysis, including H&E, Safranin O-Fast Green, and toluidine blue staining, confirmed improved cartilage integrity, while OARSI scoring indicated reduced disease severity. Immunofluorescence showed upregulated CDKN1A expression, decreased MMP13, and reduced α-SMA expression in fibroblast subtypes. Major organs exhibited no signs of toxicity, confirming the biocompatibility and safety of the treatment. These findings suggest that MSCs@CuS@CDKN1A can effectively regulate fibroblast activity and promote cartilage repair, providing a promising therapeutic strategy for OA treatment.

IMPC impact on preclinical mouse models

IMPC impact on preclinical mouse models

Amauroderma rugosum Extract Improves Brain Function in d‐Galactose‐Induced Aging Mouse Models via the Regulatory Effects of Its Polysaccharides on Oxidation, the mTOR‐Dependent Pathway, and Gut Microbiota

ABSTRACTThe pharmacological effects of Amauroderma rugosum (AR), an edible mushroom found mainly in Southeast Asia, are not well studied, particularly its neuroprotective properties. This study investigated the neuroprotective effects of AR aqueous extract (ARW) in a d‐galactose‐induced accelerated aging mouse model and senescent SH‐SY5Y neuronal cells. Behavioral tests (open field, Morris water maze, Y‐maze, and rotarod) demonstrated that d‐galactose‐induced aging mice exhibited impaired cognitive function, memory loss, anxiety, and reduced locomotor ability, all of which were alleviated by ARW treatment. Histological analysis showed that ARW reduced neuropathological lesions in the hippocampus. In SH‐SY5Y neuronal cells, ARW and AR polysaccharide extract (ARP) enhanced cell viability and decreased intracellular reactive oxygen species (ROS) levels in a concentration‐dependent manner. ARW and ARP also reduced cellular senescence and apoptosis in d‐galactose‐treated cells. Western blot analysis indicated that ARW and ARP upregulated the phosphorylation of mTOR and increased the expression of antioxidant enzymes, including superoxide dismutase 1 and heme‐oxygenase‐1. Additionally, ARW altered the gut microbiota, increasing the relative abundance of beneficial bacteria such as Lactobacillus reuteri and decreasing harmful bacteria like Clostridium scindens. These findings suggest that AR exerts neuroprotective effects primarily through its polysaccharides by modulating oxidative stress, activating the mTOR‐dependent pathway, and influencing the gut microbiota. Consequently, AR could serve as a potential dietary supplement for the prevention and treatment of neurodegenerative diseases.

Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia

Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia

Harnessing Insect Chemosensory and Mechanosensory Receptors Involved in Feeding for Precision Pest Management

Chemosensation and mechanosensation are vital to insects’ survival and behavior, shaping critical physiological processes such as feeding, metabolism, mating, and reproduction. During feeding, insects rely on diverse chemosensory and mechanosensory receptors to distinguish between nutritious and harmful substances, enabling them to select suitable food sources while avoiding toxins. These receptors are distributed across various body parts, allowing insects to detect environmental cues about food quality and adjust their behaviors accordingly. A deeper understanding of insect sensory physiology, especially during feeding, not only enhances our knowledge of insect biology but also offers significant opportunities for practical applications. This review highlights recent advancements in research on feeding-related sensory receptors, covering a wide range of insect species, from the model organism Drosophila melanogaster to agricultural and human pests. Additionally, this review examines the potential of targeting insect sensory receptors for precision pest control. Disrupting behaviors such as feeding and reproduction emerges as a promising strategy for pest management. By interfering with these essential behaviors, we can effectively control pest populations while minimizing environmental impacts and promoting ecological balance.

Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.

Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.

Transcription Factor Fingerprint Provides Clues for Brain Tumor Cell of Origin.

Mouse models that faithfully represent the biology of human brain tumors are critical tools for unraveling the underlying tumor biology and screening for potential precision therapies. This is especially true of rare tumor types, many of which have correspondingly few xenograft or cell lines available. Although our understanding of the specific biological pathways driving cancer has improved significantly, identifying the appropriate progenitor populations to drive oncogenic processes represents a significant barrier to efficient mouse model production. In this issue of Cancer Research, Jessa and colleagues developed an innovative transcription factor fingerprinting method to map the cellular origin of central nervous system neuroblastoma, FOXR2-activated to medial ganglionic eminence-derived interneurons, which could then be efficiently targeted in the developing mouse brain using in utero electroporation. This approach serves as a blueprint for investigating other rare pediatric brain tumors, potentially accelerating progress toward the development of mouse models and identification of effective therapies. See related article by Jessa et al., p. 231.

Biomechanically inspired composite hydrogel bioink enhances engineered cartilage formation

Current therapies for articular cartilage defects or degeneration (osteoarthritis) remain unsatisfactory. There are significant clinical demands for the development of more efficient approaches to enhance the repair or regeneration of articular cartilage lesions. In this study, a newly defined alginate-gelatin (A-G) composite bioink was synthesized using the carbodiimide chemistry crosslinking method. Then, the dual-crosslinking (DC) bioscaffolds containing both chemical and ionic networks were fabricated by 3D-bioprinting technique and Ca2+ treatment. The optimized networks formed in the DC bioscaffolds provided a desirable Young’s modulus and geometric constraints, which were superior to that of the single-crosslinking (SC) control group to mimic the mechanical properties of the pericellular matrix (PCM) of native articular cartilage. Chondrocytes exhibited above 95% viability and higher proliferation rate in the 3D printed A-G-DC bioscaffolds than in the alginate-only group after 7 days in vitro culture. Chondrogenic differentiation in vitro was improved in the A-G-DC bioscaffolds than that of the alginate-only group, indexed by upregulation of chondrogenic marker gene expression including Sox9, Col2a1, Comp and Aggrecan. In the subcutaneous transplantation model and osteochondral defect model in mice with severe combined immunodeficiency (SCID), the A-G-DC bioscaffolds exhibited enhanced chondrogenesis and repair capacity than the alginate-only or none-implant control group, characterized by the increased expression of SOX9 and collagen type II (Col II) and higher ICRS II scores, respectively. These findings demonstrated that the biomechanically inspired A-G composite bioink and the 3D-printed A-G-DC bioscaffolds possess excellent cell biocompatibility, satisfactory biomechanical properties and chondrogenesis promotion capacity, which have the potential to be applied to enhance cartilage regeneration for patients with articular cartilage lesions.

Pharmacokinetics of 7,8-dihydroxyflavone in neonatal mice with hypoxia-ischemia related brain injury

Introduction7,8-Dihydroxyflavone (7,8-DHF) is a promising translational therapy in several brain injury models, including the neonatal hypoxia-ischemia (HI) model in mice. However, the neuroprotective effect of 7,8-DHF was only observed in female, but not male, neonatal mice with HI brain injury. It is unknown whether HI-induced physiological changes affect brain distribution of 7,8-DHF differently for male versus female mice. We aimed to evaluate the impact of sex on the pharmacokinetics of 7,8-DHF in plasma and brain neonatal mice following experimentally induced HI brain injury.MethodsLeft-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5 mg/kg intraperitoneal injection of 7,8-DHF. A liquid chromatography-tandem mass spectrometry method was developed to quantitate the drug concentration in plasma samples, as well as in samples from the left and right brain hemispheres. A nonlinear mixed-effects model was used to analyze the plasma and brain concentration-time data. A semi-quantitative approach was used to evaluate the concentrations of two active O-methylated metabolites of 7,8-DHF (8H7M-flavone and 7H8M-flavone) in both plasma and brain samples.ResultsOur PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3 h after the IP injection. Sex was not significantly associated with the PK of 7,8-DHF; however, HI brain injury was associated with a 21% reduction in clearance (p < 0.01). The distribution of 7,8-DHF to the brain was rapid; however, the extent of brain distribution was low with the right and left brain-to-plasma partition coefficients being 8.6% and 9.9%, respectively. Additionally, both O-methylated metabolites of 7,8-DHF were detected in the plasma and brain.ConclusionThe plasma and brain PK of 7,8-DHF in neonatal mice were similar between males and females. The low extent of 7,8-DHF brain distribution and the potential effects of the active metabolites should be considered in future studies evaluating the therapeutic effects of 7,8-DHF.

New Multiomic Studies Shed Light on Cellular Diversity and Neuronal Susceptibility in Parkinson's Disease.

Parkinson's disease is a complex neurodegenerative disorder characterized by degeneration of dopaminergic neurons, with patients manifesting varying motor and nonmotor symptoms. Previous studies using single-cell RNA sequencing in rodent models and humans have identified distinct heterogeneity of neurons and glial cells with differential vulnerability. Recent studies have increasingly leveraged multiomics approaches, including spatial transcriptomics, epigenomics, and proteomics, in the study of Parkinson's disease, providing new insights into pathogenic mechanisms. Continued advancements in experimental technologies and sophisticated computational tools will be essential in uncovering a network of neuronal vulnerability and prioritizing disease modifiers for novel therapeutics development. © 2025 International Parkinson and Movement Disorder Society.

RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8

Macrophages play important roles in maintaining intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases (IBDs). However, the underlying mechanisms that govern macrophage-mediated inflammation are still largely unknown. In this study, we report that RNF128 is downregulated in proinflammatory macrophages. RNF128 deficiency leads to elevated levels of effector cytokines in vitro and accelerates the progression of IBD in mouse models. Bone marrow transplantation experiments revealed that RNF128 deficiency in bone marrow cells contributes to the worsening of DSS-induced colitis. Mechanistically, RNF128 interacts with and destabilizes S100A8 by promoting its autophagic degradation, which is mediated by the cargo receptor Tollip. Moreover, the administration of an S100A8 neutralizing antibody mitigated the development of colitis and improved survival in DSS-treated Rnf128−/− mice. Overall, our study underscores the anti-inflammatory role of RNF128 in macrophages during the progression of colitis and highlights the potential of targeting the RNF128-Tollip-S100A8 axis to attenuate intestinal inflammation for the treatment of colitis.

SIRT2 and ALDH1A1 as critical enzymes for astrocytic GABA production in Alzheimer’s disease

BackgroundAlzheimer’s Disease (AD) is a neurodegenerative disease with drastically altered astrocytic metabolism. Astrocytic GABA and H2O2 are associated with memory impairment in AD and synthesized through the Monoamine Oxidase B (MAOB)-mediated multi-step degradation of putrescine. However, the enzymes downstream to MAOB in this pathway remain unidentified.MethodsUsing transcriptomics analysis, we identified two candidate enzymes, Aldehyde Dehydrogenase 1 family member A1 (ALDH1A1) and Sirtuin 2 (SIRT2) for the steps following MAOB in the astrocytic GABA production pathway. We used immunostaining, metabolite analysis and electrophysiology, both in vitro and in vivo, to confirm the participation of these enzymes in astrocytic GABA production. We checked for the presence of SIRT2 in human AD patients as well as the mouse model APP/PS1 and finally, we selectively ablated SIRT2 in the astrocytes of APP/PS1 mice to observe its effects on pathology.ResultsImmunostaining, metabolite analysis, and electrophysiology recapitulated the participation of ALDH1A1 and SIRT2 in GABA production. Inhibition of SIRT2 reduced the production of astrocytic GABA but not H2O2, a key molecule in neurodegeneration. Elevated expression of these enzymes was found in hippocampal astrocytes of AD patients and APP/PS1 mice. Astrocyte-specific gene-silencing of SIRT2 in APP/PS1 mice restored GABA production and partially improved memory function.ConclusionsOur study is the first to identify the specific role of SIRT2 in reactive astrogliosis and determine the specific pathway and metabolic step catalyzed by the enzyme. We determine the partial, yet significant role of ALDH1A1 in this process, thereby highlighting 2 new players the astrocytic GABA production pathway. Our findings therefore, offer SIRT2 as a new tool to segregate GABA from H2O2 production, aiding future research in neurodegenerative diseases.Graphical

Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD

BackgroundRegulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into the spines upon glutamate-induced receptor activation. However, the molecular mechanism(s) behind the spine entry of dendritic mRNAs under metabotropic glutamate receptor (mGluR)-mediated neuroactivation and long-term depression (LTD) as well as the fate of these mRNAs inside the spines are still elusive.MethodDifferent molecular and imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence in situ hybridization (FISH), live cell imaging, live cell tracking of RNA using beacon, and mouse model study are used to elucidate a novel mechanism regulating dendritic spine transport of mRNAs in mammalian neurons.ResultsWe demonstrate here that brief mGluR1 activation-mediated dephosphorylation of pFMRP (S499) results in the dissociation of FMRP from TDP-43 and handover of TDP-43/Rac1 mRNA complex from the dendritic transport track on microtubules to myosin V track on the spine actin filaments. Rac1 mRNA thus enters the spines for translational reactivation and increases the mature spine density. In contrast, during mGluR1-mediated neuronal LTD, FMRP (S499) remains phosphorylated and the TDP-43/Rac1 mRNA complex, being associated with kinesin 1-FMRP/cortactin/drebrin, enters the spines owing to Ca2+-dependent microtubule invasion into spines, but without translational reactivation. In a VPA-ASD mouse model, this regulation become anomalous.ConclusionsThis study, for the first time, highlights the importance of posttranslational modification of RBPs, such as the neurodevelopmental disease-related protein FMRP, as the molecular switch regulating the dendrite-to-spine transport of specific mRNAs under mGluR1-mediated neurotransmissions. The misregulation of this switch could contribute to the pathogenesis of FMRP-related neurodisorders including the autism spectrum disorder (ASD). It also could indicate a molecular connection between ASD and neurodegenerative disease-related protein TDP-43 and opens up a new perspective of research to elucidate TDP-43 proteinopathy among patients with ASD.

PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer

BackgroundProgrammed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of immune checkpoint inhibitor (ICI) therapy in various types of cancer. Platelets are important components of the tumour microenvironment (TME) and are widely involved in the development of many types of cancer including colorectal cancer (CRC). However, the role of PD-L1 positive platelets in ICI therapy for CRC remains unknown. We hypothesized that PD-L1 positive platelets trigger and sustain CRC immunosuppression.MethodsThe functional depletion effects of PD-L1 positive platelets on TME and immune cells were measured via western blotting, immunofluorescence staining, qRT-PCR, ELISpot and flow cytometry. In vivo, CD274 knockout (KO), CD8a KO, platelet-specific KO (PF4-Cre-Hsp90b1flox/flox) mouse models and a subcutaneous tumour model treated with aspirin and PD-L1 mAb were established in C57BL/6 N mice.ResultsWe found that PD-L1 positive platelets are correlated with a poor prognosis, CD8 + T cell exhaustion and serve as a novel noninvasive biomarker for predicting immunotherapy efficacy in patients with CRC. The transfer of PD-L1 from tumour cells to platelets in the TME depends on direct cell contact via the fibronectin-1/GPIbα/integrin α5β1 pathway. In turn, platelets can also induce PD-L1 expression on cancer cells. Animal experiments revealed that antiplatelet pharmacological agents and genetic knockout of platelets potentiated the antitumour effect of the PD-L1 mAb treatment in a CD8 + T cell dependent manner.ConclusionsOur data suggest that PD-L1 positive platelets suppress CD8 + T cell immunity. Clinical combination treatment with ICIs and antiplatelet agents may be an effective therapeutic strategy for treating CRC.

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.