Cell Balance Research Articles

Thermally engineered MSC-derived extracellular vesicles ameliorate colitis in mice by restoring the imbalanced Th17/Treg cell ratio

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have garnered extensive interest for their immunomodulatory properties in immune-mediated inflammatory diseases. However, the development of EVs as clinical drugs often faces challenges such as low production yield and suboptimal therapeutic efficacy. In this study, we discovered that thermally engineering was able to enhance the yield of MSC-EVs. Moreover, the PD-L1 expression of EVs released from the thermal engineering MSCs was found to be upregulated significantly, and these EVs ameliorated the symptoms and pathological damages in murine dextran sulfate sodium (DSS)-induced colitis model. The therapeutic effect on DSS-induced colitis was mediated through the regulation of the Th17/Treg cell balance, demonstrating the immunomodulatory properties of the thermally engineering MSC-EVs. Overall, our findings suggest that thermal engineering can be utilized as a promising strategy for enhancing EV production and may provide a potential therapeutic approach for clinical treatment of colitis.

Sohlh2 promotes pulmonary fibrosis via repression of p62/Keap1/Nrf2 mediated anti-oxidative signaling pathway

Disturbance in the redox balance of alveolar epithelial cells (AECs) was considered as a causal factor for pulmonary fibrosis. The regulatory mechanisms of redox hemostasis in the development of pulmonary fibrosis remain largely unknown. Using a type II AEC-specific Sohlh2 conditional knock-in (CKI) mouse model, we found that Sohlh2, a basic HLH transcription factor, accelerated age-related pulmonary fibrosis. High-fat diet (HFD) resulted in a tremendous increase in lung inflammation and fibrotic changes in the lung tissues of Sohlh2 CKI mice. Sohlh2 overexpression led to a significant rise of intracellular ROS and apoptosis in the lung, mouse primary AECIIs, and human A549 cells, which was attenuated by ROS inhibitor (NAC). Sohlh2 enhanced oxidative stress via repressing p62/Keap1/Nrf2 mediated anti-oxidative signaling pathway. p62, a direct target of Sohlh2, mediated Sohlh2 effects on ROS generation and apoptosis in A549 cells. Hence, our findings elucidate a pivotal mechanism underlying oxidative stress-induced pulmonary fibrosis, providing a framework for aging-related disorder interventions.

Intestinal flora, intestinal metabolism, and intestinal immunity changes in complete Freud's adjuvant-rheumatoid arthritis C57BL/6 mice

Rheumatoid arthritis (RA) is an inflammatory-mediated autoimmune disease characterized by persistent joint enlargement, synovial cartilage damage, and inflammatory infiltrates. Although the pathogenesis and treatment of RA are still currently insufficient, the importance of the intestine flora, metabolism and immunity for RA has been gradually recognized, and many intestine regulatory strategies have been used to treat RA. However, the relationship between RA and intestine flora, metabolism and immunity has not been fully expounded. In this study, Complete Freund's Adjuvant (CFA) was used to establish RA model, CyTOF technology was used to study the changes of intestinal immune cell types, 16S rRNA technology was used to analyze the differences of intestinal flora, and LC-MS technology was used to explain the effects of metabolites produced by the changed intestinal flora on RA. Moreover, we systematically explored how the imbalance of intestinal flora changed the intestinal immune status through its metabolites in RA mice. Our results showed that the intestinal flora of RA mice changed significantly, and the bacteria producing short-chain fatty acids (SCFAs), indole classes and secondary bile acids were significantly reduced. The abundance of SCFAs, indole classes and secondary bile acids in the intestine were significantly decreased. The balance of immune cells in the intestine of RA mice was significantly disrupted, with an overall decrease in immune cells. This work reveals the possible relationship between intestinal flora, metabolism and immunity and RA in mice, which will provide new therapeutic strategies for RA.

Diselenium-linked dimeric prodrug nanomedicine breaking the intracellular redox balance for triple-negative breast cancer targeted therapy

Triple-negative breast cancer (TNBC) has been regarded as the strongest malignancy in cases of breast cancer with a poor prognosis. The development of effective treatment strategies for TNBC has always been an urgent and unmet need. The intracellular redox balance is essential for maintaining TNBC cell malignancy. Disrupting intracellular redox balance by enlarging reactive oxygen species (ROS) generation and facilitating glutathione (GSH) depletion to amplify intracellular oxidative stress may be an alternative strategy to eliminate TNBC cells. However, inducing ROS generation and GSH depletion concurrently may be challenging. Herein, a diselenium linked-dimeric prodrug nanomedicine FA-SeSe-NPs was developed to break the intracellular redox homeostasis for TNBC targeted therapy. The dimeric prodrug was synthesized by conjugating two cucurbitacin B (CuB) molecules via one diselenium bond, which was subsequently assembled with FA-PEG-DSPE to form the final nanomedicine FA-SeSe-NPs. Using the active targeting potential of folic acid (FA), FA-SeSe-NPs could accumulate in tumor tissue with elevated levels and then be specifically internalized by cancer cells. In the high ROS and GSH conditions of TNBC cells, the diselenium bond can specifically respond to ROS to produce selenium free radicals to increase ROS and react with GSH to generate S-Se bond to deplete GSH. The released CuB further induced ROS production in TNBC cells. The diselenium bond and CuB functioned synergistically to amplify oxidative stress to kill the TNBC cells. Here, we provide a promising strategy to disrupt the intracellular redox balance of cancer cells for effective TNBC therapy.

Exogenous Application of Humic Acid Mitigates Salinity Stress on Pittosporum (Pittosporum tobira) Plant by Adjusting the Osmolytes and Nutrient Homeostasis

AbstractImproving the physiological status expressed in adjusting the osmolytes and nutrients balance of plant cell is a crucial matter for ameliorating the hazards of salinity. In this context, humic substances have a significant role for stimulating the plant tolerance to various stresses. Therefore, the current study aimed to assess the importance of foliar spray of humic acid (0 and 150 mg L−1) for avoiding the effect of salt stress (0, 4000 and 8000 mg L−1) on vegetative growth of pittosporum plant, protein, proline, peroxidase activity and nutrient components related to salinity. The treatments were arranged in a randomized complete block design with 3 replicates. Results revealed that the highest vegetative growth was recorded with mg L−1 humic acid. While, salinity levels of 4000, and 8000 mg L−1 led to increases in protein, proline peroxidase activity, and chloride and sodium inions. Compared to humic acid-untreated plants, application of humic acid under salinity level of 4000 mg L−1 enhanced plant height, root fresh weight plant−1, root dry weight plant−1, shoot fresh weight plant−1 and shoot dry weight plant−1 by 12.6, 10.9, 17.7, 43.4, 19.4%, respectively, in the second season. Humic acid application under all salinity levels showed favorable effect for keeping leaves in both seasons, since fallen leaves number was reduced. The increases in potassium (K) content reached about 12.0 and 22.4% under 4000 mg L−1 and 8000 mg L−1, respectively, owing to humic acid application. Protein, proline content and peroxidase activity showed the minimal values under humic acid × salinity level of 4000 mg L−1. It could be concluded that application of humic mitigates the harmful effect of salinity and improves the vegetative growth parameters and physiological status of pittosporum plants while increases the uptake of beneficial nutrients.

Multiobjective design optimization of transformers for battery cell balancing converters considering bidirectional power flow

Multiobjective design optimization of transformers for battery cell balancing converters considering bidirectional power flow

BMP4 inhibits corneal neovascularization by interfering with tip cells in angiogenesis

Corneal neovascularization (CNV) can lead to impaired corneal transparency, resulting in vision loss or blindness. The primary pathological mechanism underlying CNV is an imbalance between pro-angiogenic and anti-angiogenic factors, with inflammation playing a crucial role. Notably, a vascular endothelial growth factor（VEGF）-A gradient triggers the selection of single endothelial cells（ECs） into primary tip cells that guide sprouting, while a dynamic balance between tip and stalk cells maintains a specific ratio to promote CNV. Despite the central importance of tip-stalk cell selection and shuffling, the underlying mechanisms remain poorly understood. In this study, we examined the effects of bone morphogenetic protein 4 (BMP4) on VEGF-A-induced lumen formation in human umbilical vein endothelial cells (HUVECs) and CD34-stained tip cell formation. In vivo, BMP4 inhibited CNV caused by corneal sutures. This process was achieved by BMP4 decreasing the protein expression of VEGF-A and VEGFR2 in corneal tissue after corneal suture injury. By observing the ultrastructure of the cornea, BMP4 inhibited the sprouting of tip cells and brought forward the appearance of intussusception. Meanwhile, BMP4 attenuated the inflammatory response by inhibiting neutrophil extracellular traps （NETs）formation through the NADPH oxidase-2（NOX-2）pathway. Our results indicate that BMP4 inhibits the formation of tip cells by reducing the generation of NETs, disrupting the dynamic balance of tip and stalk cells and thereby inhibiting CNV, suggesting that BMP4 may be a potential therapeutic target for CNV.

Design of Fuzzy Logic Controller for Inductor Based Cell Balancing in Battery Management System

Lithium-ion batteries are a popular energy storage used in various applications including electronic devices, electric vehicles, renewable energy systems, and microgrids. The limitations in capacity and voltage of individual battery cells necessitate arranging them in series and parallel configurations to meet the energy demands of the system. However, connecting cells in series can potentially lead to charge imbalance among cells, resulting in reduced battery pack capacity and triggering safety concerns. Numerous topologies and control methods for battery cell balancing systems have been explored in previous research. In this study, two fuzzy logic controllers with different membership function shapes are designed to drive the duty cycle of PWM signals for inductor-based cell to cell balancing. Based on simulation results, the designed controllers demonstrate good performance compared to conventional methods.

Development of fluorescent probes with specific recognition moiety for hydrogen polysulfide

Hydrogen polysulfide (H2Sn, n > 1) is an important component of reactive sulfur species (RSS), which is an important substance for maintaining the redox balance in cells. However, limited recognition moieties are available for hydrogen polysulfide probe design. In this study, we have constructed a small library containing several organic molecules to explore a new specific recognition moiety for H2Sn fluorescent probe design. To validate the discovery, two fluorescent probes, 7 and BCC, were further developed based on coumarin and its derivative. The probes exhibited desirable specificity for H2Sn monitoring, which can be used for detecting H2Sn in solution and cells. The new specific recognition moiety for H2Sn fluorescent probe design discovered in this work has certain guiding significance for development of H2Sn probes exploring biological roles in the future.

Dysregulation of circulating T follicular helper cell subsets and their potential role in the pathogenesis of syphilis.

The role of the host immune response could be critical in the development of Treponema pallidum (Tp) infection in individuals with latent syphilis. This study aims to investigate the alterations in T follicular helper T (Tfh) cell balance among patients with secondary syphilis and latent syphilis. 30 healthy controls (HCs), 24 secondary syphilis patients and 41 latent syphilis patients were enrolled. The percentages of total Tfh, ICOS+ Tfh, PD-1+ Tfh, resting Tfh, effector Tfh, naïve Tfh, effector memory Tfh, central memory Tfh,Tfh1, Tfh2, and Tfh17 cells in the peripheral blood were all determined by flow cytometry. The percentage of total Tfh cells was significantly higher in secondary syphilis patients compared to HCs across various subsets, including ICOS+ Tfh, PD-1+ Tfh, resting Tfh, effector Tfh, naïve Tfh, effector memory Tfh, central memory Tfh, Tfh1, Tfh2, and Tfh17 cells. However, only the percentages of ICOS+ Tfh and effector memory Tfh cells showed significant increases in secondary syphilis patients and decreases in latent syphilis patients. Furthermore, the PD-1+ Tfh cells, central memory Tfh cells, and Tfh2 cells showed significant increases in latent syphilis patients, whereas naïve Tfh cells and Tfh1 cells exhibited significant decreases in secondary syphilis patients when compared to the HCs. However, no significant change was found in resting Tfh and effector Tfh in HCs and secondary syphilis patients or latent syphilis patients. Dysregulated ICOS+ Tfh or effector memory Tfh cells may play an important role in immune evasion in latent syphilis patients.

The balance between CD4+ T helper 17 and T-cell immunoglobulin and mucin domain 3 is involved in the pathogenesis and development of atrial fibrillation.

To investigate the expression of Th17, T lymphocyte immunoglobulin mucin 3 (TIM-3+) cells and their related cytokines in atrial fibrillation (AF) and their clinical significance. A total of 90 patients with AF were divided into paroxysmal group (n=45) and chronic group (n=45), and 45 healthy volunteers were selected as the control group. The proportion of Th17 cells and Tim-3 + cells in the peripheral blood were detected. The concentrations of related cytokines in peripheral blood serum were determined. The correlation between Th17 / Tim-3+ cells and related cytokines was analysed. Compared with the control group, the proportion of Th17 cells and the concentration of related cytokines (IL-17, IL-6 and Matrix metalloproteinase (MMP9)) in peripheral blood of patients with paroxysmal and chronic AF increased significantly, while the proportion of tim3 + cells and the concentration of related cytokines decreased significantly. Compared with the paroxysmal group, the proportion of Th17 cells and the concentration of related cytokines in the peripheral blood of patients in the chronic group increased significantly, while the proportion of tim3 + cells and the concentration of related cytokines decreased significantly. Th17 / Tim-3 + cell balance is involved in AF, and can be used as a target for AF treatment.

Unveiling poly(rC)-binding protein 2 as the target protein for curcusone C against prostate cancer: mechanism validation through click chemistry-activity based proteomics profiling approach

BackgroundProstate cancer is a disease that seriously troubles men. However, there are some inevitable limitations in interventional therapy for prostate cancer patients at present, most of which are caused by low selectivity and high toxic side effects due to unclear drug targets. In this study, we identified the target protein of Curcusone C with anti-prostate cancer potential activity and verified its target and mechanism of action.MethodsClick chemistry-activity based proteomics profiling (CC-ABPP) method was used to find target protein of Curcusone C against prostate cancer. Competitive CC-ABPP, drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) methods were used to verifying the target protein. Moreover, potential mechanism was validated by western blot in vitro and by hematoxylin-eosin (HE) staining, detection of apoptosis in tumor tissue (TUNEL), and immunohistochemical (IHC) in vivo.ResultsWe found that poly(rC)-binding protein 2 (PCBP2) was the target protein of Curcusone C. In addition, Curcusone C might disrupt the Bax/Bcl-2 balance in PC-3 cells by inhibiting the expression of the target protein PCBP2, thereby inducing mitochondrial damage and activation of the mitochondrial apoptosis pathway, and ultimately inducing apoptosis of prostate cancer cells.ConclusionsCurcusone C is a potential compound with anti-prostate cancer activity, and this effect occurs by targeting the PCBP2 protein, which in turn may affect the TGF/Smad signaling pathway and Bax/Bcl-2 balance. Our results laid a material and theoretical foundation for Curcusone C, to be widely used in anti-prostate cancer.

Circ_SPEF2 Regulates the Balance of Treg Cells by Regulating miR-16-5p/BACH2 in Lymphoma and Participates in the Immune Response.

This study aims to explore the potential mechanism of action of the newly discovered hsa_circ_0128899 (circSPEF2) in diffuse large B-cell lymphoma (DLBCL). circSPEF2, miR-16-5p and BTB and CNC homologue 2 (BACH2) expression patterns in DLBCL patients and cell lines were studied by RT-qPCR. The biological function of circSPEF2 in vitro and in vivo was investigated by function acquisition experiments. The proliferation activity of lymphoma cells was detected by MTT. Bax, Caspase-3, and Bcl-2 were determined by Western Blot. Apoptosis and the ratio of CD4 to Treg of immune cells in the co-culture system were analyzed by flow cytometry. The mechanism of action of circSPEF2 in DLBCL progression was further investigated by RIP and dual luciferase reporter experiments. circSPEF2 was a circRNA with abnormally down-regulated expression in DLBCL. Increasing circSPEF2 expression inhibited the proliferative activity and induced apoptosis of lymphoma cells in vitro and in vivo, as well as increased CD4+T cells and decreased Treg cell proportion of immune cells in the tumor microenvironment. Mechanically, circSPEF2 was bound to miR-16-5p expression, while BACH2 was targeted by miR-16-5p. circSPEF2 overexpression-mediated effects on lymphoma progression were reversible by upregulating miR-16-5p or downregulating BACH2. circSPEF2 can influence DLBCL progression by managing cellular proliferation and apoptosis and the proportion of immune cells Treg and CD4 through the miR-16-5p/BACH2 axis.

PH-Activated Scallop-Type Nanoenzymes for Oxidative Stress Amplification and Photothermal Enhancement of Antibacterial and Antibiofilm Effect.

Ferric phosphate (FePOs) nanoenzymes can express peroxidase (POD) activity under the dual stimulation of an acidic environment and high H2O2 concentrations. In living organisms, this generates reactive oxygen species (ROS) in sites of lesion infection, and thus FePOs nanoenzymes can act as antimicrobial agents. Here, CeO2 and ZnO2 were immobilized in a scallop-type FePOs nanoenzyme material loaded with a photosensitizer, indocyanine green, to synthesize a multifunctional cascade nanoparticle system (FePOs-CeO2-ZnO2-ICG, FCZI NPs). H2O2 concentrations could be adjusted through the ZnO2 self-activation response to the slightly acidic environment in biofilms, further promoting the release of ROS from the POD-like reaction of FePOs, achieving amplification of oxidative stress, DNA and cell membrane damage, and exploiting the photodynamic/photothermal effects of indocyanine green to enhance the antibiofilm effects. CeO2 can remove redundant ROS by switching from Ce4+ to Ce3+ valence, enhancing its ability to fight chronic inflammation and oxidative stress and thus promoting the regeneration of tissues around infection. By maintaining the redox balance of normal cells, increasing ROS at the infection site, eliminating redundant ROS, and protecting normal tissues from damage, the synthesized system maximizes the elimination of biofilms and treatment at the infection site. Therefore, this work may pave the way for the application of biocompatible nanoenzymes.

Resonance Coil Design for a Novel Battery Cell Balancing with using Near-Field Coupling

Resonance Coil Design for a Novel Battery Cell Balancing with using Near-Field Coupling

Mechanisms underlying the beneficial effects of physical exercise on multiple sclerosis: focus on immune cells.

Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS is heterogeneous, it is well established that aberrant activity of adaptive and innate immune cells plays a crucial role in its pathogenesis. Several immune cell abnormalities have been described in MS and its animal models, including T lymphocytes, B lymphocytes, dendritic cells, neutrophils, microglia/macrophages, and astrocytes, among others. Physical exercise offers a valuable alternative or adjunctive disease-modifying therapy for MS. A growing body of evidence indicates that exercise may reduce the autoimmune responses triggered by immune cells in MS. This is partially accomplished by restricting the infiltration of peripheral immune cells into the central nervous system (CNS) parenchyma, curbing hyperactivation of immune cells, and facilitating a transition in the balance of immune cells from a pro-inflammatory to an anti-inflammatory state. This review provides a succinct overview of the correlation between physical exercise, immune cells, and MS pathology, and highlights the potential benefits of exercise as a strategy for the prevention and treatment of MS.

The Ferroptosis Induced by Palmitic Acid via CD36 Activating ER Stress to Break Calcium-Iron Balance in Colon Cancer Cells

There have been numerous studies to date on the treatment of tumors by saturated fatty acids. But the role that ferroptosis plays in this is not clear. Palmitic acid (PA) is a common saturated fatty acid with huge application prospects for inducing tumor cell ferroptosis. In vivo and in vitro experiments were performed to verify changes in cell proliferation, apoptosis and ferroptosis after PA treatment of colon cancer cells. Changes in ROS, lipid peroxidation, ferric ions, calcium ions, endoplasmic reticulum (ER) stress, endocytosis recycling trafficking of transferrin after PA treatment of colon cancer cells were detected. Further using necrosis inhibitor (Necrostatin-1), apoptosis inhibitor (Z-VAD-FMK), autophagy inhibitor (CQ), iron death inhibitor (Fer-1), calcium / ferric ion chelator (BAPTA-AM / DFP), iron supplement (FAC), calcium ion agonist (thapsigargin) for positive and negative verification. The association of CD36 expression and patient prognosis in colon cancer patients was subsequently evaluated by bioinformatics analysis. Detect the difference of CD36 expression in different colon cancer cells induced by PA, and further knock down or over express CD36 to explore the change of sensitivity to PA induced ferroptosis. PA inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of ROS and lipid peroxidation. The ferroptosis inhibitor Ferrostatin-1 but not Z-VAD-FMK, Necrostatin-1, or CQ rescued the cell death induced by PA. Subsequently, we verified that PA-induced ferroptosis through excess iron as cell death was inhibited by iron chelator deferiprone (DFP) but exacerbated by a supplement of ferric ammonium citrate (FAC). Mechanistically, PA leads to endoplasmic reticulum calcium release by inducing ER stress, and the increase of cytosolic calcium level positively regulates the endocytosis recycling transport of transferrin to promote the increase of intracellular iron content. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA-induced ferroptosis. Knocking down the expression of CD36 can inhibit the sensitivity of colon cancer cells to PA induced ferroptosis, and vice versa. In general, we report for the first time that PA can selectively induce ferroptosis in colon cancer cells with high expression of CD36 by activating ER stress/ER calcium release/transferrin-dependent ferroptosis. This provides a new strategy and basis for the precise treatment of tumors.

Model-free quantitative diagnosis of internal short circuit for lithium-ion battery packs under diverse operating conditions

The internal short circuit (ISC) serves as a primary source of thermal runaway in lithium-ion batteries, thereby posing a potential safety risk. The early identification of ISC faults is crucial for mitigating risks associated with fire or explosion, but quantitatively diagnosing minor energy leakage in the initial stage of ISC can be a considerable challenge in the absence of battery modeling or preliminary experiments. In light of these constraints, this study puts forth a quantitative diagnosis technique underpinned by an innovative model-free approach tailored for battery pack systems. Our method hinges on the analysis of voltage characteristics and certain premises, wherein the variance in the quantity of electrical charge retained in a cell is estimated solely through measured voltage data. The ISC current is determined through measured current data while maintaining cell balance within the packs. In addition, we propose an ISC current compensation scheme to accommodate fluctuations in ambient temperatures over time. Consequently, the ISC resistances of all cells within the packs can be computed as an index of fault to assess the degree of ISC severity. To ascertain the feasibility of our proposed method, we undertook ISC pack experiments under a wide range of conditions, encompassing aspects such as cell inconsistency, cell balancing, subzero and varying ambient temperatures, and diverse charge/discharge protocols. The results of our experiments demonstrate that the proposed model-free method exhibits considerable applicability for real-world battery operational circumstances while also maintaining a high degree of accuracy in ISC resistance estimation.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-β and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4+ CD127- Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Tyro3 receptor tyrosine kinase contributes to pathogenic phenotypes of fibroblast-like synoviocytes in rheumatoid arthritis and disturbs immune cell balance in experimental arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by synovitis and joint damage, the underlying causes of which remain unclear. Our prior investigations revealed a notable correlation between the expression of Tyro3 Protein Tyrosine Kinase (Tyro3TK) and the progression of RA. To further elucidate the pathogenic role of Tyro3TK in RA, we analyzed the influence of Tyro3TK on pathogenic phenotypes of RA fibroblast like synoviocyte (FLS) in vitro and compared disease severity, joint damages and immunological parameters of K/BxN serum transfer arthritis (STA) in Tyro3TK−/− deficient mice and wild type controls. Our findings underscored the remarkable effectiveness of Tyro3TK blockade, as evidenced by diminished secretion of inflammatory cytokines and matrix metalloproteinases (MMPs), curtailed migration and invasiveness of RAFLS, and attenuated differentiation of pathogenic helper T cell subsets mediated by RAFLS. Correspondingly, our in vivo investigations illuminated the more favorable outcomes in Tyro3TK-deficient mice, characterized by reduced joint pathology, tempered synovial inflammation, and restored immune cell equilibrium. These data suggested that Tyro3TK might contribute to aggravated autoimmune arthritis and immunological pathology and act as a potential therapeutic target for RA.