Signal-regulatory protein alpha (SIRPα) has recently been found to be highly expressed in podocytes and is essential for maintaining podocyte function. However, its immunoregulatory function in podocytes remains elusive. Here, we report that SIRPα controls podocyte antigen presentation in specific T cell activation via inhibiting spleen tyrosine kinase (Syk) phosphorylation. First, podocyte SIRPα under lupus nephritis (LN) conditions is strongly downregulated. Second, podocyte-specific deletion of SIRPα exacerbates renal disease progression in lupus-prone mice, as evidenced by an increase in T cell infiltration. Third, SIRPα deletion or knockdown enhances podocyte antigen presentation, which activates specific T cells, via enhancing Syk phosphorylation. Supporting this, Syk inhibitor GS-9973 prevents podocyte antigen presentation, resulting in a decrease of T cell activation and mitigation of renal disease caused by SIRPα knockdown or deletion. Our findings reveal an immunoregulatory role of SIRPα loss in promoting podocyte antigen presentation to activate specific T cell immune responses in LN.

Platelet hyperreactivity contributes to the pathogenesis of COVID-19, which is associated with a hypercoagulability state and thrombosis disorder. It has been demonstrated that Vitamin D deficiency is associated with the severity of COVID-19 infection. Vitamin D supplement is widely used as a dietary supplement due to its safety and health benefits. In this study, we investigated the direct effects and underlying mechanisms of 1,25(OH)2D3 on platelet hyperreactivity induced by SRAS-CoV-2 spike protein via Western blot and platelet functional studies in vitro. Firstly, we found that 1,25(OH)2D3 attenuated platelet aggregation and Src-mediated signaling. We further observed that 1,25(OH)2D3 attenuated spike protein-potentiated platelet aggregation in vitro. Mechanistically, 1,25(OH)2D3 attenuated spike protein upregulated-integrin αIIbβ3 outside-in signaling such as platelet spreading and the phosphorylation of β3, c-Src and Syk. Moreover, using PP2, the Src family kinase inhibitor to abolish spike protein-stimulated platelet aggregation and integrin αIIbβ3 outside-in signaling, the combination of PP2 and 1,25(OH)2D3 did not show additive inhibitory effects on spike protein-potentiated platelet aggregation and the phosphorylation of β3, c-Src and Syk. Thus, our data suggest that 1,25(OH)2D3 attenuates platelet aggregation potentiated by spike protein via downregulating integrin αIIbβ3 outside-in signaling.

Death due to severe influenza is usually a fatal complication of a dysregulated immune response more than the acute virulence of an infectious agent. Although spleen tyrosine kinase (SYK) as a critical immune signaling molecule and therapeutic target plays roles in airway inflammation and acute lung injury, the role of SYK in influenza virus infection is not clear. Here, we investigated the antiviral and anti-inflammatory effects of SYK inhibitor R406 on influenza infection through a coculture model of human alveolar epithelial (A549) and macrophage (THP-1) cell lines and mouse model. The results showed that R406 treatment increased the viability of A549 and decreased the pathogenicity and mortality of lethal influenza virus in mice with influenza A infection, decreased levels of intracellular signaling molecules under the condition of inflammation during influenza virus infection. Combination therapy with oseltamivir further ameliorated histopathological damage in the lungs of mice and further delayed the initial time to death compared with R406 treatment alone. This study demonstrated that phosphorylation of SYK is involved in the pathogenesis of influenza, and R406 has antiviral and anti-inflammatory effects on the treatment of the disease, which may be realized through multiple pathways, including the already reported SYK/STAT/IFNs-mediated antiviral pathway, as well as TNF-α/SYK- and SYK/Akt-based immunomodulation pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-β-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-β-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.

UNASSIGNED: Psoriasis is a chronic inflammatory skin disease that has no cure. While the specific cause of psoriasis is unknown, interactions between immune cells and inflammatory cytokines are believed to be important in its pathogenesis. Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that profoundly affects dendritic cells (DCs) and is involved in allergy and inflammatory diseases. In some studies, its expression is higher in the skin of psoriasis patients, whereas it is increased in treated psoriasis patients when compared with untreated patients in others.
UNASSIGNED: To investigate the role of TSLP in the pathogenesis of psoriasis.
UNASSIGNED: In vitro and in vivo study.
UNASSIGNED: To investigate the effect of TSLP on psoriasis in vivo, a mouse psoriasis model and shRNA targeting TSLP to reduce its expression were used. Mouse primary bone marrow dendritic cells (BMDCs) were cultured in vitro and used to investigate the signaling pathways activated by TSLP. Results: We found that reducing TSLP expression in psoriasis skin alleviated disease severity. TSLP activated the Janus kinase (JAK)/SYK pathway in psoriatic skin. In vitro studies with BMDCs demonstrated that TSLP increased DC maturation through the JAK/SYK pathway and activated DCs-secreted cytokines that stimulated CD4+ T cells to develop into T helper 17 (Th17) cells by activating STAT3 signaling. The JAK/SYK pathway inhibitor reduced the effect of TSLP on activating BMDCs and promoting Th17 differentiation by CD4+ T cells.
UNASSIGNED: These findings indicated that TSLP exerted its immune-modulating effect in psoriasis through the JAK/SYK pathway.

Isoliquiritigenin (ISL) is a chalcone-type flavonoid derived from the root of licorice with antioxidant, anti-inflammatory, anti-tumour and neuroprotective properties. ISL has been proven to downregulate the productions of IL-1β, TNF-α and IL-6 by macrophages. However, detailed molecular mechanisms of this modulation remain elusive. Here, ISL suppressed Syk phosphorylation and CD80, CD86, IL-1β, TNF-α and IL-6 expressions in lipopolysaccharide-stimulated macrophages ex vivo. ApoC3-transgenic (ApoC3TG) mice had more activated macrophages. ISL was also able to downregulate the inflammatory activities of macrophages from ApoC3TG mice. Administration of ISL inhibited Syk activation and inflammatory activities of macrophages in ApoC3TG mice in vivo. The treatment of ISL further alleviated MCD-induced non-alcoholic fatty liver disease (NAFLD) in wild-type and ApoC3TG mice, accompanied by less recruitment and activation of liver macrophages. Due to the inhibition of Syk phosphorylation, ISL-treated macrophages displayed less production of cytoplasmic ROS, NLRP3, cleaved-GSDMD and cleaved-IL-1β, suggesting less inflammasome activation. Finally, the molecular docking study demonstrated that ISL bound to Syk directly with the Kd of 1.273 × 10-8 M. When the Syk expression was knocked down by its shRNA, the inhibitory effects of ISL on activated macrophages disappeared, indicating that Syk was at least one of key docking-molecules of ISL. Collectively, ISL could alleviate MCD-induced NAFLD in mice involved with the inhibition of macrophage inflammatory activity by the blockade of Syk-induced inflammasome activation.

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a relatively inert B lymphocyte proliferative disease. In recent years with the launch of new drugs, chemotherapy has been gradually replaced by targeted therapy, which significantly prolongs the survival of patients and reduces the side effects of treatment. At present, BTK inhibitors, PI3K inhibitors, spleen tyrosine kinase (SYK) inhibitors and BCL-2 inhibitors are the most studied targeted therapeutic drugs for CLL/SLL. This article reviews the research progress of different types of targeted therapeutic drugs in the treatment of CLL/SLL.
UNASSIGNED: 慢性淋巴细胞白血病/小淋巴细胞淋巴瘤靶向治疗的最新研究进展.
UNASSIGNED: .慢性淋巴细胞白血病（CLL）/小淋巴细胞淋巴瘤（SLL）是一种相对惰性的B淋巴细胞增殖性疾病。近年来，随着新药的上市，化疗逐渐被靶向治疗所取代，明显延长了患者生存期并减低了治疗副作用。目前研究较多的CLL/SLL靶向治疗药物有BTK抑制剂、PI3K抑制剂、SYK抑制剂和BCL-2抑制剂。本文就不同种类靶向治疗药物在CLL/SLL治疗中的最新研究进展作一综述。.

BACKGROUND: SIRPB1 expression is upregulated in various tumor types, including gliomas, and is known to contribute to tumor progression; nevertheless, its function in the immune milieu of gliomas is still mainly unknown.
METHODS: This study, we analyzed 1152 normal samples from the GTEx database and 670 glioma samples from the TCGA database to investigate the relationship between the expression of SIRPB1 and clinicopathological features. Moreover, SIRPB1 gene knockout THP-1 cell lines were constructed using CRISPR/Cas9 and were induced into a co-culture of macrophages and glioma cells in vitro to learn more about the role of SIRPB1 in the glioma immune milieu. Lastly, we established a prognostic model to predict the effect of SIRPB1 on prognosis.
RESULTS: Significantly higher levels of SIRPB1 expression were found in gliomas, which had an adverse effect on the immune milieu and correlated poorly with patient survival. SIRPB1 activation with certain antibodies results in SYK phosphorylation and the subsequent activation of calcium, MAPK, and NF-κB signaling pathways. This phenomenon is primarily observed in myeloid-derived cells as opposed to glioma cells. In vitro co-culture demonstrated that macrophages with SIRPB1 knockout showed decreased IL1RA, CCL2, and IL-8, which were recovered upon ectopic expression of SIRPB1 but reduced again following treatment with SYK inhibitor GS9973. Critically, a lower overall survival rate was linked to increased SIRPB1 expression. Making use of SIRPB1 expression along with additional clinicopathological variables, we established a nomogram that showed a high degree of prediction accuracy.
CONCLUSIONS: Our study demonstrates that glioma cells can be activated by macrophages via SIRPB1, subsequently reprogramming the TME, suggesting that SIRPB1 could serve as a promising therapeutic target for gliomas.

BACKGROUND: Traumatic brain injury (TBI), as a major public health problem, is characterized by high incidence rate, disability rate, and mortality rate. Neuroinflammation plays a crucial role in the pathogenesis of TBI. Triggering receptor expressed on myeloid cells-1 (TREM-1) is recognized as an amplifier of the inflammation in diseases of the central nervous system (CNS). However, the function of TREM-1 remains unclear post-TBI. This study aimed to investigate the function of TREM-1 in neuroinflammation induced by TBI.
METHODS: Brain water content (BWC), modified neurological severity score (mNSS), and Morris Water Maze (MWM) were measured to evaluate the effect of TREM-1 inhibition on nervous system function and outcome after TBI. TREM-1 expression in vivo was evaluated by Western blotting. The cellular localization of TREM-1 in the damaged region was observed via immunofluorescence staining. We also conducted Western blotting to examine expression of SYK, p-SYK and other downstream proteins.
RESULTS: We found that inhibition of TREM-1 reduced brain edema, decreased mNSS and improved neurobehavioral outcomes after TBI. It was further determined that TREM-1 was expressed on microglia and modulated subtype transition of microglia. Inhibition of TREM-1 alleviated neuroinflammation, which was associated with SYK/p38MAPK signaling pathway.
CONCLUSIONS: These findings suggest that TREM-1 can be a potential clinical therapeutic target for alleviating neuroinflammation after TBI.

Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process. Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE-/- DM) was generated from ApoE knockout (ApoE-/-) mice using a high-fat and high-glucose diet combined with low-dose streptozocin intraperitoneal injection. We also established an in vitro model using HK2 cells. A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE-/- DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE-/- DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and downregulated the expression of PKCβ/P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high-glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing downregulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406). In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD-associated oxidative stress and apoptosis via downregulation of PKCβ/P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.