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关键词： Paraquat   IL-17A   Microglial phagocytosis   CD36   Amyloid-(3   alpha-Synuclein  

摘要： Paraquat (PQ), an environmental neurotoxin, has been demonstrated to induce pathological protein aggregation and thus neurotoxicity. Nevertheless, the exact mechanisms remain elusive. In this investigation, we explored the involvement of interleukin-17A (IL-17 A) in the aggregation of amyloid-(3 (A(3) and alpha-synuclein (alpha-syn) induced by PQ. Combining in vitro and in vivo, we explored whether PQ leads to A(3 and alpha-syn aggregation through IL-17 A-mediated reduction in microglia phagocytosis, thereby aggravating neurotoxicity. The results demonstrated that low-dose PQ continuous exposure significantly elevated IL-17 A levels in the peripheral blood serum and prefrontal cortical regions of mice. It also suppressed microglial phagocytosis of pathological proteins and promoted the aggregation of A(3 and alpha-syn in the prefrontal cortex. These changes ultimately resulted in depression, anxiety, and cognitive impairments. Mechanistically, IL-17 A inhibited the expression of the microglial phagocytic receptor CD36, impairing the microglial ability to clear A(3 and alpha-syn. Furthermore, administering an anti-IL-17 A effectively restored microglial phagocytosis in PQ-exposed mice, reduced A(3 and alpha-syn aggregation in prefrontal cortical areas, and alleviated behavioral deficits. In conclusion, this paper highlights IL-17 A as a pivotal mediator in PQ-induced neurotoxicity. It provides a potential target for developing novel therapeutic strategies against neurodegenerative pathologies induced by such environmental toxicants.

关键词： soluble MHC class I chain-related protein A   sMICA   biomarker   graft-versus host disease   GvHD   allogeneic hematopoetic stem cell transplantation  

摘要： Introduction MHC class I chain-related protein A (MICA) acts as a marker of cellular stress and its expression is a destruction-signal for NKG2D-expressing cytotoxic cells. Soluble MICA (sMICA) concentrations after allogeneic hematopoietic stem cell transplantation (HSCT) were associated with worse outcomes and graft-versus-host disease (GVHD). We hypothesized that (i) sMICA could be a prognostic biomarker for the development of GVHD and (ii) may act as an acute phase reactant. Methods In this prospective study we included 48 patients undergoing HSCT and drew blood samples before conditioning (baseline), during engraftment and 100 days after HSCT. The follow-up period was 1 year for each patient. Soluble MICA and established acute phase reactants (C-reactive Protein, von Willebrand Factor) were measured by enzyme-linked immunoassay (ELISA). Results Of the 44 patients in the final analysis, 30 (68%) developed GVHD (16 acute GVHD, 8 chronic GVHD, 6 acute and chronic GVHD). Soluble MICA concentrations at baseline and during engraftment were significantly higher in patients who developed acute or chronic GVHD (p = 0.017). Receiver operating characteristic (ROC) curve analysis for the baseline values showed an area under the curve of 0.78 (p < 0.001;95% confidence intervals 0.64-0.91) for diagnosis of acute or chronic GVHD. Soluble MICA concentrations above 93.5 pg/mL had a specificity of 93% for the diagnosis of GVHD, while the sensitivity was only 47%. Discussion Soluble MICA did not correlate with other acute phase reactants and remained stable during engraftment. Soluble MICA may potentially serve as a biomarker with high specificity for the prediction of GVHD.

关键词： angiogenesis   early gastric cancer   endothelial cells   IL-33   tumor microenvironment   organoids   single-cell RNA sequencing  

摘要： Early gastric cancer (EGC) represents a critical stage in preventing and controlling the progression from gastritis to advanced gastric cancer (AGC). Therefore, identifying the single-cell characteristics of EGC, particularly the cellular composition of the tumor microenvironment (TME), as well as identifying potential predictive markers and therapeutic targets, could significantly enhance the monitoring of gastric cancer and improve clinical cure rates. We constructed a comprehensive single-cell RNA sequencing atlas for 184,426 high-quality gastric cancer cells from various stages, utilizing clinical biopsies and surgical samples. Our single-cell atlas highlights the cellular and molecular characteristics of EGC. Eight distinct cell lineage states were identified, and it was observed that the number of epithelial cell meta-clusters gradually decreased, while the number of T&NK, B, plasma, fibroblast, myeloid, and endothelial cells increased with disease progression. Certain epithelial subclusters (metaplastic stem-like cells (MSCs), pit mucous-like cells (PMC-like), proliferating cells), T-cell subclusters (Treg, CCR7+ naive, CH25H+ CD4+, TEM CD8+, and GFPT2+ CD8+ T cells), and endothelial subclusters (IL-33+ Venous-1 and AMAMTSL2+ Artery-2) were found to be increased in EGC. The Venous-1 subcluster was found to express high levels of IL-33. Mechanistically, it was revealed that IL-33 enhances the survival and angiogenesis of endothelial cells by upregulating the expression of adhesion proteins CD34 and PECAM1. Patient-derived EGC and AGC organoids were subsequently generated, and it was demonstrated that endothelial-derived IL-33 promoted the growth of both EGC and AGC organoids ex vitro and in vivo. Furthermore, IL-33 was found to increase the expression of KRT17 in EGC organoids. Notably, we also found that high expression of IL-33 was positively correlated with the depth of invasion and malignancy of EGC. This study provides novel insights into the single-cell

摘要： In this issue of Blood, Garcia-Lacarte et al identify autocrine and paracrine activities of lymphoma cell-derived interleukin-10 (IL-10) in a murine diffuse large B-cell lymphoma (DLBCL) model that may be exploited for tailoring immunotherapy interventions.(1)

关键词： Yellow fever virus   A549 cells   Mitochondrial network dynamics   Mitophagy   IFN-I   TLR2  

摘要： It has been emphasized that mitochondria play a fundamental role not only in cellular bioenergetics but also in the defense against infections. Here, we investigated mitochondrial network dynamics (MND) and IFN-I(3 signaling response in epithelial A549 cells after yellow fever virus (YFV) infection. We analyze the MND when only some cells are infected at 1 day post-infection (dpi) and after the spread of viral infection, at 3 dpi. Confocal microscopy and MiNA analysis showed that YFV infection leads to a decrease in the number of branches at 3 dpi and an increase in the length of branches at 1 and 3 dpi, suggesting that mitochondrial fission and fusion occur. Consistent with both processes, we found increased transcription of mitofusin 1 and Drp1 and increased colocalization of mitochondria with Drp1 at 3 dpi. In addition, mitochondrial membrane polarization decreased, mtROS production increased, p62 expression decreased, and LC3 expression increased, suggesting an increase in mitophagy flux. We found decreased expression of the IFN inducers RIG-I and MAVS sensors in YFV-infected A549 cells a t 3 dpi. Surprisingly, increased IFN-I(3 levels were observed at transcriptional and protein levels along with IRF7 induction at 1 and 3 dpi. Using the blocking antibody against TLR2, we showed that IFN-I(3 and IL-6 synthesis is maintained by TLR2 signaling. Mechanistically, infection led to activation of the NFxB pathway by degradation of IkBa, and increased phosphorylation of P65 and ERK MAPK signaling. Our results show that YFV infection induces altered MND in epithelial cells and triggers TLR2 signaling.

关键词： IL-17   IL-33   eosinophil   neutrophil  

关键词： vascularized composite allotransplantation   gamma delta T cell   classical monocyte   IL-17   mouse   IFN-gamma   perforin   granzyme  

摘要： Background Vascularized Composite Allotransplantation (VCA) is an important therapeutic option for patients that incur debilitating injuries to the face or limbs. The complexity and immunogenicity of tissue types within VCA grafts pose unique challenges and necessitate the use of intensive immunosuppression;however, graft rejection remains a challenge in VCA. Methods Deep proteomic profiling and high dimensional analysis with cytometry time of flight were used to define the cell types and effector mechanisms elicited by VCA in BALB/c (H-2Kd) > C57BL/6 (H-2Kb) limb recipients. Spleen and cervical draining lymph nodes were collected post-transplant days 1, 3, 5, and 7 (n =4-6 mice/group/day). We identified dynamic, coordinated signatures in T cell and monocyte populations associated with VCA allograft rejection. ResultsIn comparison to syngeneic transplant recipients, allogeneic recipients exhibited significant alterations in the immune cell populations within secondary lymphoid tissues. These changes included very early expansion of double-negative TCR beta(-) T cells, including IL-17A-producing gamma delta T cells, and patrolling monocytes. Subsequently, CD8+CD62L+ T cells and CD8+ effector/effector memory T cells (Teff/Tem), Ly6C(hi)CCR2(hi)CX3CR1(low) classical monocytes, CD4+ Teff/Tem, and CD8+CD25(hi)CCR7(low) Teff/Tem were increased by day 5. CD8+CD25(hi)CCR7(low) Teff/Tem with the highest expression of IFN-gamma, perforin, and granzyme B were enriched by day 7. Conclusions High dimensional proteomic analysis reveals multiple innate and Teff/Tem subsets in acute rejection following VCA. In particular, IL-17A-producing gamma delta T cells and classical monocytes may be particularly important in initiating the alloimmune response in VCA recipients.

关键词： Epidemiology   prevalence   risk factors   hormones   sex   gender   tear film   pathophysiology   neurogenic   clinical trials   iatrogenic   ADDE   Aqueous-deficient dry eye disease   BALB/c   BALB/C wildtype (mice)   CXL   Corneal cross-linking   DED   Dry eye disease   DEQ-5   5-Item Dry Eye Questionnaire   DEWS   Dry eye workshops   DNA   Deoxyribonucleic acid   EDE   Evaporative dry eye disease   FDA   Food and drug administration   (f)MRI   (Functional) magnetic resonance imaging   GVHD   Graft versus host disease   HLA   Human leukocyte antigen   HPMC   Hydroxypropyl methylcellulose   ICAM-1   Intercellular Adhesion Molecule 1   IL   Interleukin   IGF   Insulin-like growth factor   IVCM   In vivo   confocal microscopy   LASIK   Laser-assisted   in situ   keratomileusis   LIPCOF   Lid-parallel conjunctival folds   LLT   Lipid layer thickness   MGD   Meibomian gland dysfunction   MGYLS   Meibomian glands yielding liquid secretions   MMP   Matrix metalloproteinase   MUC4   Mucin 4   NGF   Nerve growth factor   NIBUT   Non-invasive tear film breakup time   NF-kB   Nuclear factor kappa-light-chain-enhancer of activated B cells   NRS   Numerical rating scale   OCT   Optical coherence tomography   OR   Odds ratio   OSDI   Ocular Surface Disease Index   PRK   Photorefractive keratectomy   QoL   Quality of Life   SANDE   Symptom Assessment iN Dry Eye questionnaire   SPEED   Standard Patient Evaluation of Eye Dryness questionnaire   TBUT   Tear film breakup time   TED   Thyroid eye disease   TFOS   Tear Film & Ocular Surface Society   TRPM8   Transient Receptor Potential cation channel subfamily M member 8   VAS   Visual analogue scale  

摘要： This digest summarises the interdisciplinary research in dry eye disease (DED) published since the 2017 TFOS DEWS II reports. It comprises seven topics including Sex, Gender, and Hormones, Epidemiology, Pathophysiology, Tear Film, Pain and Sensation, Iatrogenic and Clinical Trial Design and explores how each of these inform diagnostic methodology, disease subtype and management of DED. Sex- and gender-related differences significantly influence the ocular surface due to hormones, sex chromosomes, sex-specific autosomal factors, epigenetics, care-seeking behaviors, and service utilization. Epidemiological data reveal that DED prevalence varies by age and sex, influenced by diagnostic criteria and the multifactorial nature of the disease. New risk factors for DED include environmental, iatrogenic, systemic diseases and lifestyle domains. Pathophysiological distinctions between Aqueous Deficient Dry Eye (ADDE) and Evaporative Dry Eye (EDE) have been clarified. EDE is characterized by a muted inflammatory response at the ocular surface, meibomian gland dysfunction and conceivably phenotypic changes in corneal epithelial cells. There is an expanding role for metabolic, hormonal, physical, neural and cellular stresses, including hyperosmolarity, mitochondrial stress, and neurogenic inflammation. Advancements in tear film research recommend new approaches to understanding DED pathogenesis and identifying biomarkers, such as microRNAs. Ocular pain perception is linked to structural integrity of corneal nerves, functional capacities of neurons, and activity of the central and peripheral nervous systems. Iatrogenic DED can result from medications, contact lenses, and surgical procedures. Clinical trials now emphasize aligning design and endpoints with DED subtypes and therapeutic mechanisms, with new therapeutics and trial designs under consideration.

关键词： allogeneic cell therapy   allorejection   B2M   beta-2-microglobulin   CAR-T cells   chimeric antigen receptor-engineered T cells   CIITA   class II major histocompatibility complex transactivator   genetic engineering   HLA   human leukocyte antigen   natural killer cells   NK cells   off-the-shelf cell therapy  

摘要： Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of various diseases, including cancers and autoimmune disorders. However, all US Food and Drug Administration (FDA)-approved CAR-T cell therapies are autologous, and their widespread clinical application is limited by several challenges, such as complex individualized manufacturing, high costs, and the need for patient-specific selection. Allogeneic off-the-shelf CAR-engineered cell therapy offers promising potential due to its immediate availability, consistent quality, potency, and scalability in manufacturing. Nonetheless, significant challenges, including the risks of graft-versus-host disease (GvHD) and host-cellmediated allorejection, must be addressed. Strategies such as knocking out endogenous T cell receptors (TCRs) or using alternative therapeutic cells with low GvHD risk have shown promise in clinical trials aimed at reducing GvHD. However, mitigating allorejection remains critical for ensuring the long-term sustainability and efficacy of off-the-shelf cell products. In this review, we discuss the immunological basis of allorejection in CAR-engineered therapies and explore various strategies to overcome this challenge. We also highlight key insights from recent clinical trials, particularly related to the sustainability and immunogenicity of allogeneic CAR-engineered cell products, and address manufacturing considerations aimed at minimizing allorejection and optimizing the efficacy of this emerging therapeutic approach.