scholarly journals Lupus-like autoimmune disease caused by a lack of Xkr8, a caspase-dependent phospholipid scramblase

2018 ◽  
Vol 115 (9) ◽  
pp. 2132-2137 ◽  
Author(s):  
Mahiru Kawano ◽  
Shigekazu Nagata
Keyword(s):  
Autoimmune Disease ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Granulocyte Colony Stimulating Factor ◽  
Wild Type ◽  
Phospholipid Scramblase ◽  
Complex Deposition ◽  
Stimulating Factor ◽  
Deficient Mice

Apoptotic cells expose phosphatidylserine (PtdSer) on their cell surface and are recognized by macrophages for clearance. Xkr8 is a scramblase that exposes PtdSer in a caspase-dependent manner. Here, we found that among the three Xkr members with caspase-dependent scramblase activity, mouse hematopoietic cells express only Xkr8. The PtdSer exposure of apoptotic thymocytes, splenocytes, and neutrophils was strongly reduced when Xkr8 was absent. While wild-type apoptotic lymphocytes and neutrophils were efficiently engulfed in vitro by phagocytes expressing Tim4 and MerTK, Xkr8-deficient apoptotic cells were hardly engulfed by these phagocytes. Accordingly, the number of apoptotic thymocytes in the thymus and neutrophils in the peritoneal cavity of the zymosan-treated mice was significantly increased in Xkr8-deficient mice. The percentage of CD62Llo senescent neutrophils was increased in the spleen of Xkr8-null mice, especially after the treatment with granulocyte colony-stimulating factor. Xkr8-null mice on an MRL background showed high levels of autoantibodies, splenomegaly with high levels of effector CD4 T cells, and glomerulonephritis development with immune-complex deposition at glomeruli. These results indicate that the Xkr8-mediated PtdSer exposure in apoptotic lymphocytes and aged neutrophils is essential for their clearance, and its defect activates the immune system, leading to lupus-like autoimmune disease.

scholarly journals Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

2014 ◽  
Vol 306 (6) ◽  
pp. L508-L520 ◽  
Author(s):  
David I. Kasahara ◽  
Hye Y. Kim ◽  
Joel A. Mathews ◽  
Norah G. Verbout ◽  
Alison S. Williams ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Γδ T Cells ◽  
Pivotal Role ◽  
Ozone Exposure ◽  
Granulocyte Colony Stimulating Factor ◽  
Wild Type ◽  
Neutrophilic Inflammation ◽  
Stimulating Factor ◽  
Deficient Mice

Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24–72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin-deficient ( Adipo−/−) mice. The IL-17/granulocyte colony-stimulating factor (G-CSF) axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo−/−mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 ( Adipo−/−/IL-6−/−) and exposed them to ozone or air. In ozone-exposed mice, bronchoalveolar lavage (BAL) neutrophils, IL-6, and G-CSF, and pulmonary Il17a mRNA expression were greater in Adipo−/−vs. wild-type mice, but reduced in Adipo−/−/IL-6−/−vs. Adipo−/−mice. IL-17A+F4/80+cells and IL-17A+γδ T cells were also reduced in Adipo−/−/IL-6−/−vs. Adipo−/−mice exposed to ozone. Only BAL neutrophils were reduced in IL-6−/−vs. wild-type mice. In wild-type mice, IL-6 was expressed in Gr-1+F4/80−CD11c−cells, whereas in Adipo−/−mice F4/80+CD11c+cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 ( Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo−/−vs. wild-type mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo−/−vs. wild-type mice but reduced in Adipo−/−/IL-6−/−vs. Adipo−/−mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo−/−mice after ozone exposure and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A, and G-CSF.

scholarly journals Lymphocyte–HEV Interactions in Lymph Nodes of a Sulfotransferase-deficient Mouse

2003 ◽  
Vol 198 (9) ◽  
pp. 1289-1300 ◽  
Author(s):  
Annemieke van Zante ◽  
Jean-Marc Gauguet ◽  
Annette Bistrup ◽  
Durwin Tsay ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Dependent Manner ◽  
Deficient Mouse ◽  
Wild Type ◽  
Lymphocyte Homing ◽  
High Endothelial Venules ◽  
Blocking Antibody ◽  
Selectin Ligands ◽  
Deficient Mice

The interaction of L-selectin expressed on lymphocytes with sulfated sialomucin ligands such as CD34 and GlyCAM-1 on high endothelial venules (HEV) of lymph nodes results in lymphocyte rolling and is essential for lymphocyte recruitment. HEC-GlcNAc6ST–deficient mice lack an HEV-restricted sulfotransferase with selectivity for the C-6 position of N-acetylglucosamine (GlcNAc). HEC-GlcNAc6ST−/− animals exhibit faster lymphocyte rolling and reduced lymphocyte sticking in HEV, accounting for the diminished lymphocyte homing. Isolated CD34 and GlyCAM-1 from HEC-GlcNAc6ST−/− animals incorporate ∼70% less sulfate than ligands from wild-type animals. Furthermore, these ligands exhibit a comparable reduction of the epitope recognized by MECA79, a function-blocking antibody that reacts with L-selectin ligands in a GlcNAc-6-sulfate–dependent manner. Whereas MECA79 dramatically inhibits lymphocyte rolling and homing to lymph nodes in wild-type mice, it has no effect on HEC-GlcNAc6ST−/− mice. In contrast, in vitro rolling on purified GlyCAM-1 from HEC-GlcNAc6ST−/− mice, although greatly diminished compared with that on the wild-type ligand, is inhibited by MECA79. Our results demonstrate that HEC-GlcNAc6ST contributes predominantly, but not exclusively, to the sulfation of HEV ligands for L-selectin and that alternative, non-MECA79–reactive ligands are present in the absence of HEC-GlcNAc6ST.

scholarly journals Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 312
Author(s):  
Hikaru Tamura ◽  
Tomoki Maekawa ◽  
Hisanori Domon ◽  
Takumi Hiyoshi ◽  
Satoru Hirayama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Resorption ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Dependent Manner ◽  
Wild Type ◽  
Immunomodulatory Effects ◽  
Related Factors ◽  
Deficient Mice

Macrolides are used to treat various infectious diseases, including periodontitis. Furthermore, macrolides are known to have immunomodulatory effects; however, the underlying mechanism of their action remains unclear. DEL-1 has emerged as an important factor in homeostatic immunity and osteoclastogenesis. Specifically, DEL-1 is downregulated in periodontitis tissues. Therefore, in the present study, we investigated whether the osteoclastogenesis inhibitory effects of erythromycin (ERM) are mediated through upregulation of DEL-1 expression. We used a ligature-induced periodontitis model in C57BL/6Ncrl wild-type or DEL-1-deficient mice and in vitro cell-based mechanistic studies to investigate how ERM inhibits alveolar bone resorption. As a result of measuring alveolar bone resorption and gene expression in the tooth ligation model, ERM treatment reduced bone loss by increasing DEL-1 expression and decreasing the expression of osteoclast-related factors in wild-type mice. In DEL-1-deficient mice, ERM failed to suppress bone loss and gene expression of osteoclast-related factors. In addition, ERM treatment downregulated osteoclast differentiation and calcium resorption in in vitro experiments with mouse bone marrow-derived macrophages. In conclusion, ERM promotes the induction of DEL-1 in periodontal tissue, which may regulate osteoclastogenesis and decrease inflammatory bone resorption. These findings suggest that ERM may exert immunomodulatory effects in a DEL-1-dependent manner.

scholarly journals Nucleotide-Binding Oligomerization Domain Protein 2-Deficient Mice Control Infection with Mycobacterium tuberculosis

2007 ◽  
Vol 75 (11) ◽  
pp. 5127-5134 ◽  
Author(s):  
Sheetal Gandotra ◽  
Sihyug Jang ◽  
Peter J. Murray ◽  
Padmini Salgame ◽  
Sabine Ehrt
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nucleotide Binding ◽  
Dependent Manner ◽  
Wild Type ◽  
Cytoplasmic Proteins ◽  
Antigen Presenting ◽  
Deficient Mice ◽  
Oligomerization Domain

ABSTRACT Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. NOD2 has recently been shown to be important for host cell cytokine responses to Mycobacterium tuberculosis, to synergize with Toll-like receptor 2 (TLR2) in mediating these responses, and thus to serve as a nonredundant recognition receptor for M. tuberculosis. Here, we demonstrate that macrophages and dendritic cells from NOD2-deficient mice were impaired in the production of proinflammatory cytokines and nitric oxide following infection with live, virulent M. tuberculosis. Mycolylarabinogalactan peptidoglycan (PGN), the cell wall core of M. tuberculosis, stimulated macrophages to release tumor necrosis factor (TNF) and interleukin-12p40 in a partially NOD2-dependent manner, and M. tuberculosis PGN required NOD2 for the optimal induction of TNF. However, NOD2-deficient mice were no more susceptible to infection with virulent M. tuberculosis than wild-type mice: they controlled the replication of M. tuberculosis in lung, spleen, and liver as well as wild-type mice, and both genotypes displayed similar lung pathologies. In addition, mice doubly deficient for NOD2 and TLR2 were similarly able to control an M. tuberculosis infection. Thus, NOD2 appears to participate in the recognition of M. tuberculosis by antigen-presenting cells in vitro yet is dispensable for the control of the pathogen during in vivo infection.

scholarly journals The Granulocyte Colony-Stimulating Factor Receptor Is Required for the Mobilization of Murine Hematopoietic Progenitors Into Peripheral Blood by Cyclophosphamide or Interleukin-8 But Not Flt-3 Ligand

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2522-2528 ◽  
Author(s):  
Fulu Liu ◽  
Jennifer Poursine-Laurent ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Interleukin 8 ◽  
Cytotoxic Agents ◽  
Common Mechanism ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Cyclophosphamide Administration

Hematopoietic progenitor cells (HPC) can be mobilized from the bone marrow into the peripheral circulation in response to a number of stimuli including hematopoietic growth factors, cytotoxic agents, and certain chemokines. Despite significant differences in their biological activities, these stimuli result in the mobilization of HPC with a similar phenotype, suggesting that a common mechanism for mobilization may exist. In this study, the role of granulocyte colony-stimulating factor (G-CSF) in progenitor mobilization was examined using G-CSF receptor (G-CSFR)–deficient mice. In contrast to wild-type mice, no increase in circulating colony-forming cells (CFU-C), CD34+ lineage− progenitors, or day 12 colony-forming unit-spleen progenitors (CFU-S) was detected in G-CSFR–deficient mice after cyclophosphamide administration. This defect was not due to a failure to regenerate HPC following cyclophosphamide administration as the number of CFU-C in the bone marrow of G-CSFR–deficient mice was increased relative to wild-type mice. Likewise, no increase in circulating CFU-C was detected in G-CSFR–deficient mice following interleukin-8 (IL-8) administration. In contrast, mobilization of HPC in response to flt-3 ligand was nearly normal. These results show that the G-CSFR is required for mobilization in response to cyclophosphamide or IL-8 but not flt-3 ligand and suggest that the G-CSFR may play an important and previously unexpected role in HPC migration.

scholarly journals The Granulocyte Colony-Stimulating Factor Receptor Is Required for the Mobilization of Murine Hematopoietic Progenitors Into Peripheral Blood by Cyclophosphamide or Interleukin-8 But Not Flt-3 Ligand

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2522-2528 ◽  
Author(s):  
Fulu Liu ◽  
Jennifer Poursine-Laurent ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Interleukin 8 ◽  
Cytotoxic Agents ◽  
Common Mechanism ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Cyclophosphamide Administration

Abstract Hematopoietic progenitor cells (HPC) can be mobilized from the bone marrow into the peripheral circulation in response to a number of stimuli including hematopoietic growth factors, cytotoxic agents, and certain chemokines. Despite significant differences in their biological activities, these stimuli result in the mobilization of HPC with a similar phenotype, suggesting that a common mechanism for mobilization may exist. In this study, the role of granulocyte colony-stimulating factor (G-CSF) in progenitor mobilization was examined using G-CSF receptor (G-CSFR)–deficient mice. In contrast to wild-type mice, no increase in circulating colony-forming cells (CFU-C), CD34+ lineage− progenitors, or day 12 colony-forming unit-spleen progenitors (CFU-S) was detected in G-CSFR–deficient mice after cyclophosphamide administration. This defect was not due to a failure to regenerate HPC following cyclophosphamide administration as the number of CFU-C in the bone marrow of G-CSFR–deficient mice was increased relative to wild-type mice. Likewise, no increase in circulating CFU-C was detected in G-CSFR–deficient mice following interleukin-8 (IL-8) administration. In contrast, mobilization of HPC in response to flt-3 ligand was nearly normal. These results show that the G-CSFR is required for mobilization in response to cyclophosphamide or IL-8 but not flt-3 ligand and suggest that the G-CSFR may play an important and previously unexpected role in HPC migration.

scholarly journals Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara Busacca ◽  
Qi Zhang ◽  
Annabel Sharkey ◽  
Alan G. Dawson ◽  
David A. Moore ◽  
...  
Keyword(s):  
Small Molecule ◽  
Selective Vulnerability ◽  
Dependent Manner ◽  
Histone H4 ◽  
Wild Type ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Methylthioadenosine Phosphorylase ◽  
Protein Arginine Methyltransferase 5

AbstractWe hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

scholarly journals AB0095 PRECLINICAL CHARACTERIZATION OF CJ-15314, A HIGHLY SELECTIVE JAK1 INHIBITOR, FOR THE TREATMENT OF AUTOIMMUNE DISEASES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1347.2-1347
Author(s):  
S. Y. Ki ◽  
H. Shin ◽  
Y. Lee ◽  
H. R. Bak ◽  
H. Yu ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Whole Blood ◽  
Inflammatory Diseases ◽  
Selective Inhibition ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Human Whole Blood

Background:Janus kinases (JAK1, JAK2, JAK3, and TYK2) play critical roles in mediating various cytokine signaling, and has been developed as a target for autoimmune diseases such as RA. Tofacitinib, oral Pan-JAK inhibitor, demonstrated efficacy in RA patients, but its widespread use is limited by safety issues. Baricitinib, JAK1/2 inhibitor, is also known to interfere with the hematopoiesis system, such as anemia and thrombocytopenia associated with suppression of JAK2 signals. Therefore, it is necessary to develop a new potent compound that selectively inhibits JAK1 over JAK2, 3Objectives:To identify the pharmacological characteristic based on efficacy of CJ-15314 as potent and selective JAK1 inhibitor for treatment of autoimmune disease.Methods:In vitro, cell-based, kinase panel, Kd value and human whole blood assay were performed to determine the inhibition potency and selectivity for JAK subfamily kinases. In vivo therapeutic potential was evaluated by RA model including rat Adjuvant-Induced Arthritis (AIA) and collagen-induced arthritic (CIA). To confirm the possibility of further expansion into the autoimmune disease, BioMAP® Diversity PLUS® Panel was performed by discoverX.Results:In vitro assay, CJ-15314 inhibited JAK kinase family in a concentration-dependent manner with IC50 values of 3.8 nM against JAK1, Selectivity for JAK1 over JAK2, 3 was approximately 18, 83 fold greater for CJ-15314. In 1mM ATP condition, CJ-15314 has been confirmed to have the highest JAK1 selectivity over competing drugs, under 1 mM ATP condition that reflects the physiological environment in the body. Similarly, Kd values has also confirmed the selectivity of JAK1, which is 10 fold higher than JAK2, 3. Accordingly, in human whole blood assays, CJ-15314 is 11 fold more potent against IL-6 induced pSTAT1 inhibition through JAK1 (IC50 value: 70 nM) than GM-CSF-induced pSTAT5 inhibition (JAK2) whereas baricitinib and filgotinib exhibited only 2 fold and 7 fold respectively.In vivo efficacy model, CJ-15314 inhibited disease severity scores in a dose dependent manner. In the rat AIA model, CJ-15314 at 30 mg/kg dose showed 95.3% decrease in arthritis activity score, 51.2% in figotinib at 30 mg/kg, 97.7% showed baricitinib at 10 mg/kg. CJ-15314 showed superior anti-arthritic efficacy than filgotinib. CJ-15314 also minimally affected anemia-related parameters but not bricitinib end of the 2-week treatment. In the rat CIA model, like 10 mg/kg of bricitinib, 30 mg/kg of CJ-15314 also has a similar effect, with a significant reduction in histopathological scores.In biomap diversity panel, CJ-15314 inhibited the expression of genes such as MCP-1, VCAM-1, IP-10, IL-8, IL-1, sTNF-α and HLA-DR confirming the possibility of expansion into other diseases beyond arthritis.Conclusion:CJ-15314 is a highly selective JAK1 inhibitor, demonstrates robust efficacy in RA animal model and is good candidate for further development for inflammatory diseases.* CJ-15314 is currently conducting a phase I trial in south Korea.References:[1]Clark JD et al. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014; 57(12):5023-38.[2]Burmester GR et al. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol. 2014; 10(2):77-88[3]Jean-Baptiste Telliez et al. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol., 2016; 11 (12):3442-3451Disclosure of Interests:so young Ki Employee of: CJ healthcare, hyunwoo shin Employee of: CJ healthcare, yelim lee Employee of: CJ healthcare, Hyoung rok Bak Employee of: CJ healthcare, hana yu Employee of: CJ healthcare, Seung Chan Kim Employee of: CJ healthcare, juhyun lee Employee of: CJ healthcare, donghyun kim Employee of: CJ healthcare, Dong-hyun Ko Employee of: CJ Healthcare, dongkyu kim Employee of: CJ healthcare

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