scholarly journals Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sho Hiroyasu ◽  
Matthew R. Zeglinski ◽  
Hongyan Zhao ◽  
Megan A. Pawluk ◽  
Christopher T. Turner ◽  
...  
Keyword(s):  
Immune Cell ◽  
Granzyme B ◽  
Neutrophil Infiltration ◽  
Inflammatory Protein ◽  
Anchoring Proteins ◽  
Macrophage Inflammatory Protein ◽  
Autoimmune Blistering Diseases

AbstractPemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Macrophage Inflammatory Protein (MIP)-3α/CCL20 and Its Receptor CCR6 Are Overexpressed in the Bone Microenvironment and Involved in Osteoclast Formation in Multiple Myeloma Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3510-3510 ◽  
Author(s):  
Nicola Giuliani ◽  
Gina Lisignoli ◽  
Sara Tagliaferri ◽  
Mirca Lazzaretti ◽  
Francesca Morandi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Osteoclast Formation ◽  
Bone Lesions ◽  
Mrna Levels ◽  
Bone Microenvironment ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract Osteoclast (OC) activation in multiple myeloma (MM) is primarily due to the imbalance of the critical osteoclastogenic system RANKL/OPG in the bone microenvironment. Recent evidences indicate that chemokines, small chemoattractant proteins involved in cancer cell homing, may contribute to osteoclast formation and activation. However, whereas the role of the chemokine macrophage inflammatory protein (MIP)-1α in MM-induced OC activation is well established, the involvement of other chemokines is not known. In this study, we evaluated the potential role of MIP-3α/CCL20 and its receptor CCR6 in the pathophysiology of OC formation and osteolytic lesions in MM. First the effect of MIP-3α/CCL20 on in vitro osteoclast formation by peripheral monocytes was evaluated. (MIP)-3α/CCL20 significantly increased both the number of multinucleated TRAP+ OCs and RANK+ OC progenitor cells in presence of RANKL. In addition we found that (MIP)-3α/CCL20 increases RANKL mRNA levels in both human osteoblastic (OB) and bone marrow (BM) osteoprogenitor cells (preOB). Following, the potential production of (MIP)-3α/CCL20 by human MM cell lines (HMCLs) and fresh purified CD138+ MM cells was also checked. Significant levels of (MIP)-3α/CCL20 were detected in one out of nine HMCLs tested and in about 10% of purified MM cells by ELISA and immunohystochemistry. On the other hand we found that MM cells up-regulated (MIP)-3α/CCL20 secretion, in OB/PreOB cells and in OCs as well as its receptor CCR6 in OCs in co-culture systems in presence of a transwell insert. Among potential soluble factors involved in the up-regulation of MIP-3α/CCL20 by MM cells we found that IL-1β and TNFα together stimulate MIP-3α/CCL20 production in both OB and PreOB. The role of MIP-3α/CCL20 in OC activation by MM cells was finally demonstrated by finding that both blocking anti-(MIP)-3α/CCL20 and anti-CCR6 Abs. but not anti-IgG control significantly decreased OC formation induced by the conditioned medium of MM cells co-cultured with OB and OC, respectively. This chemokine system was further studied in vivo in MM patients. MIP-3α/CCL20 levels were detected in the BM plasma of MGUS subjects (n°=16) and in MM (n°=52) patients at the diagnosis in relationship with the presence of bone lesions (osteolytic n°= 32; non-osteolytic: n°=20). Significant higher MIP-3α/CCL20 levels were detected in MM patients vs. MGUS (mean ± SD: 51.9±2 vs. 21±3 pg/mL; p=0.01) and in MM osteolytic patients vs. non-osteolytic ones (mean ± SD: 70.8±5.9 vs. 13.8±1.1 pg/mL; p=0.001). Interestingly, no significant differences were observed between MGUS and non-osteolytic MM patients. By immunohystochemistry performed on BM biopsies, we consistently found that MIP-3α/CCL20 was over-expressed in OBs in osteolytic MM patients as compared to non-osteolytic ones. In addition we found that OCs showed a strong CCR6 staining in the areas with an increased number of OCs. In conclusion our data indicate that (MIP)-3α/CCL20 its receptor CCR6 are up-regulated in bone microenvironment by MM cells and involved in osteoclast formation and bone lesions in MM patients.

Macrophage Inflammatory Protein-1α Expression in Vivo and in Vitro: The Role of Lipoteichoic Acid

1995 ◽  
Vol 74 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Jean M. Danforth ◽  
Robert M. Strieter ◽  
Steven L. Kunkel ◽  
Douglas A. Arenberg ◽  
Glenn M. VanOtteren ◽  
...  
Keyword(s):  
Lipoteichoic Acid ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

scholarly journals Inactivation of heparan sulfate 2-O-sulfotransferase accentuates neutrophil infiltration during acute inflammation in mice

Blood ◽  
2012 ◽  
Vol 120 (8) ◽  
pp. 1742-1751 ◽  
Author(s):  
Jakob Axelsson ◽  
Ding Xu ◽  
Bit Na Kang ◽  
Julia K. Nussbacher ◽  
Tracy M. Handel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Heparan Sulfate ◽  
Acute Inflammation ◽  
Neutrophil Infiltration ◽  
Neutrophil Recruitment ◽  
Rolling Velocity ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract Neutrophil recruitment and extravasation at sites of inflammation provide a mechanism for host defense. We showed previously that heparan sulfate, a type of sulfated glycosaminoglycan, facilitates neutrophil recruitment based on the reduction of neutrophil infiltration in mice in which the overall sulfation of the chains was reduced by selective inactivation of N-acetylglucosamine N-deacetylase-N-sulfotransferase (Ndst1) in endothelial cells. Here we show that inactivation of uronyl 2-O-sulfotransferase in endothelial cells (Hs2st), an enzyme that acts downstream from Ndst1, results in enhanced neutrophil recruitment in several models of acute inflammation. Enhanced neutrophil infiltration resulted in part from reduced rolling velocity under flow both in vivo and in vitro, which correlated with stronger binding of neutrophil L-selectin to mutant endothelial cells. Hs2st-deficient endothelial cells also displayed a striking increase in binding of IL-8 and macrophage inflammatory protein-2. The enhanced binding of these mediators of neutrophil recruitment resulted from a change in heparan sulfate structure caused by increased N-sulfation and 6-O-sulfation of glucosamine units in response to the decrease in 2-O-sulfation of uronic acid residues. This gain-of-function phenotype provides formidable evidence demonstrating the importance of endothelial heparan sulfate in inflammation and suggests a novel enzyme target for enhancing the innate immune response.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals Medawar’s PostEra: Galectins Emerged as Key Players During Fetal-Maternal Glycoimmune Adaptation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ellen Menkhorst ◽  
Nandor Gabor Than ◽  
Udo Jeschke ◽  
Gabriela Barrientos ◽  
Laszlo Szereday ◽  
...  
Keyword(s):  
Immune Cell ◽  
Successful Pregnancy ◽  
Fetal Health ◽  
The Past ◽  
Mammalian Embryogenesis ◽  
Carbohydrate Ligands ◽  
Membrane Bound

Lectin-glycan interactions, in particular those mediated by the galectin family, regulate many processes required for a successful pregnancy. Over the past decades, increasing evidence gathered from in vitro and in vivo experiments indicate that members of the galectin family specifically bind to both intracellular and membrane bound carbohydrate ligands regulating angiogenesis, immune-cell adaptations required to tolerate the fetal semi-allograft and mammalian embryogenesis. Therefore, galectins play important roles in fetal development and placentation contributing to maternal and fetal health. This review discusses the expression and role of galectins during the course of pregnancy, with an emphasis on maternal immune adaptions and galectin-glycan interactions uncovered in the recent years. In addition, we summarize the galectin fingerprints associated with pathological gestation with particular focus on preeclampsia.

scholarly journals Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis

2019 ◽  
Vol 11 (515) ◽  
pp. eaax2945 ◽  
Author(s):  
Yi-Ling Chen ◽  
Danuta Gutowska-Owsiak ◽  
Clare S. Hardman ◽  
Melanie Westmoreland ◽  
Teena MacKenzie ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Therapeutic Potential ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Severity Index ◽  
Fundamental Biology ◽  
Targeted Inhibition

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

scholarly journals Use of 5-fluorouracil to analyze the effect of macrophage inflammatory protein-1 alpha on long-term reconstituting stem cells in vivo

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1497-1504 ◽  
Author(s):  
VF Quesniaux ◽  
GJ Graham ◽  
I Pragnell ◽  
D Donaldson ◽  
SD Wolpe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Inhibitory Effect ◽  
In Vivo Model ◽  
Hematopoietic Progenitors ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract A macrophage-derived inhibitor of early hematopoietic progenitors (colony-forming unit-spleen, CFU-A) called stem cell inhibitor was found to be identical to macrophage inflammatory protein-1 alpha (MIP-1 alpha). We investigated the effect of MIP-1 alpha on the earliest stem cells that sustain long-term hematopoiesis in vivo in a competitive bone marrow repopulation assay. Because long-term reconstituting (LTR) stem cells are normally quiescent, an in vivo model was first developed in which they are triggered to cycle. A first 5-fluorouracil (5-FU) injection was used to eliminate later progenitors, causing the LTR stem cells, which are normally resistant to 5-FU, to enter the cell cycle and become sensitive to a second 5-FU injection administered 5 days later. Human MIP-1 alpha administered from day 0 to 7 was unable to prevent the depletion of the LTR stem cells by the second 5-FU treatment, as observed on day 7 in this model, suggesting that the LTR stem cells were not prevented from being triggered into cycle despite the MIP-1 alpha treatment. However, the MIP-1 alpha protocol used here did substantially decrease the number of more mature hematopoietic progenitors (granulocyte-macrophage colony-forming cells [CFC], burst- forming unit-erythroid, CFCmulti, and preCFCmulti) recovered in the bone marrow shortly after a single 5-FU injection. In vitro, MIP-1 alpha had no inhibitory effect on the ability of these progenitors to form colonies. This study confirms the in vivo inhibitory effect of MIP- 1 alpha on subpopulations of hematopoietic progenitors that are activated in myelodepressed animals. However, MIP-1 alpha had no effect on the long-term reconstituting stem cells in vivo under conditions in which it effectively reduced all later progenitors.

scholarly journals Potential Role of the Chemokine Macrophage Inflammatory Protein 1α in Human and Experimental Schistosomiasis

2005 ◽  
Vol 73 (4) ◽  
pp. 2515-2523 ◽  
Author(s):  
Adriano L. S. Souza ◽  
Ester Roffê ◽  
Vanessa Pinho ◽  
Danielle G. Souza ◽  
Adriana F. Silva ◽  
...  
Keyword(s):  
Potential Role ◽  
Severe Disease ◽  
Experimental Studies ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Deficient Mice

ABSTRACT In human schistosomiasis, the concentrations of the chemokine macrophage inflammatory protein 1α (MIP-1α/CCL3) is greater in the plasma of patients with clinical hepatosplenic disease. The objective of the present study was to confirm the ability of CCL3 to detect severe disease in patients classified by ultrasonography (US) and to evaluate the potential role of CCL3 in Schistosoma mansoni-infected mice. CCL3 was measured by enzyme-linked immunosorbent assay in the plasma of S. mansoni-infected patients. CCL3-deficient mice were infected with 25 cercariae, and various inflammatory and infectious indices were evaluated. The concentration of CCL3 was higher in the plasma of S. mansoni-infected than noninfected patients. Moreover, CCL3 was greater in those with US-defined hepatosplenic than with the intestinal form of the disease. In CCL3-deficient mice, the size of the granuloma and the liver eosinophil peroxidase activity and collagen content were diminished compared to wild-type mice. In CCL3-deficient mice, the worm burden after 14 weeks of infection, but not after 9 weeks, was consistently smaller. The in vitro response of mesenteric lymph node cells to antigen stimulation was characterized by lower levels of interleukin-4 (IL-4) and IL-10. CCL3 is a marker of disease severity in infected humans, and experimental studies in mice suggest that CCL3 may be a causative factor in the development of severe schistosomiasis.

scholarly journals The CCL20-CCR6 Axis in Cancer Progression

2020 ◽  
Vol 21 (15) ◽  
pp. 5186 ◽  
Author(s):  
Suguru Kadomoto ◽  
Kouji Izumi ◽  
Atsushi Mizokami
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
G Protein Coupled Receptors ◽  
Virus Infections ◽  
Cancer Breast ◽  
Inflammatory Protein ◽  
Immunodeficiency Virus ◽  
G Protein Coupled ◽  
Macrophage Inflammatory Protein

Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.

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