Obinutuzumab effective for lupus nephritis
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Syk inhibitor attenuates lupus in FcγRIIb−/− mice through the Inhibition of DNA extracellular traps from macrophages and neutrophils via p38MAPK-dependent pathway
Spleen tyrosine kinase (Syk), an important hub of immune signaling, is activated by several signalings in active lupus which could be interfered by Syk inhibitor but is still not completely evaluated in innate immune cells associated with lupus activity. Hence, a Syk inhibitor (fostamatinib; R788) was tested in vivo using Fc gamma receptor-deficient (FcγRIIb−/−) lupus mice and in vitro (macrophages and neutrophils). After 4 weeks of oral Syk inhibitor, 40 week-old FcγRIIb−/− mice (a full-blown lupus model) demonstrated less prominent lupus parameters (serum anti-dsDNA, proteinuria, and glomerulonephritis), systemic inflammation, as evaluated by serum TNFa, IL-6, and citrullinated histone H3 (CitH3), gut permeability defect, as indicated by serum FITC dextran assay, serum lipopolysaccharide (LPS), and serum (1 → 3)-β-D-glucan (BG), extracellular traps (ETs) and immune complex deposition in spleens and kidneys (immunofluorescent staining of CitH3 and immunoglobulin G) than FcγRIIb−/− mice with placebo. Due to the spontaneous elevation of LPS and BG in serum, LPS plus BG (LPS + BG) was used to activate macrophages and neutrophils. After LPS + BG stimulation, FcγRIIb−/− macrophages and neutrophils demonstrated predominant abundance of phosphorylated Syk (Western blotting), and the pro-inflammatory responses (CD86 flow cytometry analysis, supernatant cytokines, ETs immunofluorescent, and flow cytometry-based apoptosis). With RNA sequencing analysis and western blotting, the Syk-p38MAPK-dependent pathway was suggested as downregulating several inflammatory pathways in LPS + BG-activated FcγRIIb−/− macrophages and neutrophils. Although both inhibitors against Syk and p38MAPK attenuated macrophage and neutrophil inflammatory responses against LPS + WGP, the apoptosis inhibition by p38MAPK inhibitor was not observed. These results suggested that Syk inhibitor (fostamatinib) improved the severity of lupus caused by FcγRIIb defect partly through Syk-p38MAPK anti-inflammation that inhibited both ET formation and cytokine production from innate immune cells.
Treatment with obinutuzumab plus venetoclax reshapes the TRB repertoire of CLL patients
Results The TRB repertoire was characterized in 137 samples, representing 59 patients from the HOVON-139/GIVE trial at trial entry, after one year of obinutuzumab plus…
The integrated stress response pathway controls cytokine production in tissue-resident memory CD4+ T cells
Tissue-resident memory T (TRM) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4+ TRM cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in TRM cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR–eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4+ TRM cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4+ TRM cells facilitate rapid cytokine production during local immune response.
Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us?
Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.
Emerging roles of extracellular vesicles in oral and maxillofacial areas
The oral and maxillofacial region is a highly complex area composed of multiple tissue types and bears various critical functions of the human body. Diseases in this region pose significant diagnostic and management challenges; therefore, exploring new strategies for early diagnosis, targeted treatment, and tissue reconstruction is key to improving patient prognosis and quality of life. Extracellular vesicles are a group of heterogeneous lipid-bilayer membrane structures secreted by most cell types, including exosomes, microvesicles, and apoptotic bodies. Present in various body fluids and tissues, they act as messengers via the transfer of nucleic acids, proteins, and metabolites to recipient cells. To date, studies have revealed the different roles of extracellular vesicles in physiological or pathological processes, as well as applications in disease diagnosis, prognosis, and treatment. The importance and tissue specificity of the dental and maxillofacial tissues indicate that extracellular vesicles derived from this region are promising for further research. This paper reviews the published data on extracellular vesicles derived from cells, body fluids, and tissues in oral and maxillofacial regions, summarizes the latest advances in extracellular vesicles from extensive sources, and concludes with a focus on the current research progress and application prospects of engineered exosomes in oral science.
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