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Project description:The innate immune system is finely tuned to enable. rapid response to pathogenic stimuli but keep quiescent during tissue homeostasis. Balance of activating and inhibitory signaling sets a threshold for immune activation. Signal regulatory protein (SIRPa) is an immune inhibitory receptor expressed by myeloid cells and interacts with CD47 to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPa and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether therapeutic SIRPa receptor agonism could restrain excessive autoimmune inflammation in the context of autoimmunity. Here, we reported that increased neutrophil- and monocyte-associated genes including SIRPA in inflamed tissues biopsies of rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA in colonic biopsies is associated with treatment refractory ulcerative colitis patients. We next identified a novel agonistic anti-SIRPa antibody that exhibited potent anti-inflammatory effects in reducing neutrophil and monocytes chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPa agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis through reducing neutrophils and monocytes in tissues. Our work provides a proof-of-concept for SIRPa receptor agonism for suppressing excessive innate immune activation and autoimmune inflammatory therapeutic treatment
2023-08-24 | GSE236924 | GEO
Project description:The innate immune system is finely tuned to enable rapid response to pathogenic stimuli but keep quiescent during tissue homeostasis.Balance of activating and inhibitory signaling sets a threshold for immune activation. Signal regulatory protein (SIRPa) is an immune inhibitory receptor expressed by myeloid cells and interacts with CD47 to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPa and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether therapeutic SIRPa receptor agonism could restrain excessive autoimmune inflammation in the context of autoimmunity. Here, we reported that increased neutrophil- and monocyte-associated genes including SIRPA in inflamed tissues biopsies of rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA in colonic biopsies is associated with treatment refractory ulcerative colitis patients. We next identified a novel agonistic anti-SIRPa antibody that exhibited potent anti-inflammatory effects in reducing neutrophil and monocytes chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPa agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis through reducing neutrophils and monocytes in tissues. Our work provides a proof-of-concept for SIRPa receptor agonism for suppressing excessive innate immune activation and autoimmune inflammatory therapeutic treatment
2023-08-24 | GSE235400 | GEO
Project description:SIRPa agonist antibody treatment ameliorates experimental arthritis and colitis
| PRJNA993132 | ENA
Project description:SIRPa agonist antibody treatment ameliorates experimental arthritis and colitis [array]
| PRJNA993141 | ENA
Project description:SIRPa agonist antibody treatment ameliorates experimental arthritis and colitis [sequencing]
| PRJNA985933 | ENA
Project description:Crohn's disease (CD) and ulcerative colitis (UC) are two distinct forms of inflammatory bowel disease (IBD) characterized by an expanded lymphatic network with impaired functionality both in mouse models and in human patients. In this study, we investigated whether targeted delivery of the pro-lymphangiogenic vascular endothelial growth factor C (VEGFC) to the site of inflammation may represent a new, clinically feasible strategy for treating IBD. To achieve targeting of inflamed tissue, we developed a fusion protein consisting of human VEGFC fused to the F8 antibody (F8-VEGFC), which specifically binds to the extradomain A (EDA) of fibronectin, a spliced isoform almost exclusively expressed in inflamed tissues. The therapeutic activity of intravenously administered F8-VEGFC, compared to a targeted construct lacking VEGFC (F8-SIP), was investigated in a mouse model of dextran sodium sulfate (DSS)-induced colitis. The presence of EDA fibronectin was detected in both human and mouse inflamed colon tissue. Biodistribution studies of radiolabeled F8-VEGFC revealed a specific accumulation of the antibody in the colon of DSS-administered mice, as compared to an untargeted VEGFC fusion protein (KSF-VEGFC) (binding the irrelevant hen egg lysozyme antigen). Systemic treatment with F8-VEGFC significantly reduced the clinical and histological signs of inflammation, expanded the lymphatic vascular network, reduced the density of immune cells, and also decreased the expression of inflammatory cytokines in the inflamed colon. Overall, these results reveal that administration of F8-VEGFC represents a novel and promising approach for the treatment of IBD.
| S-EPMC7088901 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-12-05 | GSE241217 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. This disease is characterized by an excessive accumulation of extracellular matrix deposition that modify normal lung physiology. Up to date, there are not efficient therapeutic tools to fight IPF. Glucagon-like peptide-1 receptor (GLP-1R) activation plays an essential role in lung functions in normal and in pathological conditions. The aim of the present study was to study the possible beneficial effects of the administration of the GLP-1R agonist, liraglutide, in the pathogenesis of the fibrotic process in an animal model of pulmonary fibrosis induced by bleomycin. We observed that liraglutide decreased mRNA expression of collagen, hydroxyproline and key enzymes for the synthesis of collagen. In addition, GLP-1R activation restored the ACE2 mRNA levels modulating the activities of the RAS components, increased the production of surfactant proteins (SFTPa1, SFTPb, SFTPc) and promoted an improvement in pulmonary and cardiac functionality, including a partial restoration of lung alveolar structure. Liraglutide effects are shown at both the pro-inflammatory and fibrosis phases of the experimental disease. For these reasons, GLP-1 might be regarded as a promising drug for treating pulmonary fibrosis.
| S-EPMC7581713 | biostudies-literature
Project description:Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or dimethyl sulfoxide (DMSO) (vehicle) was administered intraperitoneally from d 2 to 6. Clinical parameters were monitored daily. Mice were euthanized on d 8 for histological evaluation and measurements of colon length, chemokine, cytokine and inflammatory mediator expression. C75 significantly reduced body weight loss from 23% to 15% on d 8, compared with the vehicle group. The fecal bleeding, diarrhea and colon histological damage scores in the C75-treated group were significantly lower than scores in the vehicle animals. Colon shortening was significantly improved after C75 treatment. C75 protected colon tissues from DSS-induced apoptosis by inhibiting caspase-3 activity. Macrophage inflammatory protein 2, keratinocyte-derived chemokine, myeloperoxidase activity and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β and IL-6) in the colon were significantly downregulated in the C75-treated group, compared with the vehicle group. Treatment with C75 in colitis mice inhibited the elevation of FASN, cyclooxygenase-2 and inducible nitric oxide synthase expression as well as IκB degradation in colon tissues. C75 administration alleviates the severity of colon damage and inhibits the activation of inflammatory pathways in DSS-induced colitis. Thus, inhibition of FASN may represent an attractive therapeutic potential for treating IBD.
| S-EPMC3912252 | biostudies-literature
Project description:V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.
| S-EPMC10858940 | biostudies-literature