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1.
J Allergy Clin Immunol ; 148(2): 506-522.e8, 2021 08.
Article in English | MEDLINE | ID: mdl-33617860

ABSTRACT

BACKGROUND: Mas gene-related G protein-coupled receptors (MRGPRs) are a G protein-coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgE-independent signaling and pseudoallergic drug reactions. OBJECTIVES: Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus. METHODS: To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human. RESULTS: We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans. CONCLUSION: Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions.


Subject(s)
Antidepressive Agents/adverse effects , Behavior, Animal/drug effects , Cell Degranulation/drug effects , Drug Hypersensitivity/immunology , Mast Cells/immunology , Nerve Tissue Proteins/immunology , Receptors, G-Protein-Coupled/immunology , Receptors, Neuropeptide/immunology , Animals , Antidepressive Agents/pharmacology , Cell Line , Drug Hypersensitivity/pathology , Humans , Mast Cells/pathology , Mice , Nerve Tissue Proteins/agonists , Receptors, G-Protein-Coupled/agonists , Receptors, Neuropeptide/agonists
2.
Cells ; 8(10)2019 10 17.
Article in English | MEDLINE | ID: mdl-31627327

ABSTRACT

The lymphocyte function-associated antigen 1 (LFA-1) is a member of the beta2-integrin family and plays a pivotal role for T cell activation and leukocyte trafficking under inflammatory conditions. Blocking LFA-1 has reduced or aggravated inflammation depending on the inflammation model. To investigate the effect of LFA-1 in myocarditis, mice with experimental autoimmune myocarditis (EAM) were treated with a function blocking anti-LFA-1 antibody from day 1 of disease until day 21, the peak of inflammation. Cardiac inflammation was evaluated by measuring infiltration of leukocytes into the inflamed cardiac tissue using histology and flow cytometry and was assessed by analysis of the heart weight/body weight ratio. LFA-1 antibody treatment severely enhanced leukocyte infiltration, in particular infiltration of CD11b+ monocytes, F4/80+ macrophages, CD4+ T cells, Ly6G+ neutrophils, and CD133+ progenitor cells at peak of inflammation which was accompanied by an increased heart weight/body weight ratio. Thus, blocking LFA-1 starting at the time of immunization severely aggravated acute cardiac inflammation in the EAM model.


Subject(s)
Anti-Bacterial Agents/pharmacology , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Lymphocyte Function-Associated Antigen-1/metabolism , Nervous System Autoimmune Disease, Experimental/immunology , Nervous System Autoimmune Disease, Experimental/pathology , AC133 Antigen/metabolism , Animals , Body Weight/drug effects , CD11b Antigen/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Flow Cytometry , Inflammation/immunology , Inflammation/pathology , Leukemic Infiltration/immunology , Leukemic Infiltration/pathology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred BALB C , Monocytes/drug effects , Monocytes/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Organ Size/drug effects , Stem Cells/drug effects , Stem Cells/metabolism
3.
J Exp Med ; 216(2): 350-368, 2019 02 04.
Article in English | MEDLINE | ID: mdl-30647120

ABSTRACT

Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor-related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation.


Subject(s)
Autoimmune Diseases/immunology , Cell Movement/immunology , Extracellular Traps/immunology , Midkine/immunology , Myocarditis/immunology , Myocardium/immunology , Neutrophils/immunology , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Cell Movement/genetics , Extracellular Traps/genetics , Humans , Low Density Lipoprotein Receptor-Related Protein-1/genetics , Low Density Lipoprotein Receptor-Related Protein-1/immunology , Mice , Mice, Transgenic , Midkine/genetics , Myocarditis/genetics , Myocarditis/pathology , Myocardium/pathology , Neutrophils/pathology , Receptors, LDL/genetics , Receptors, LDL/immunology , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/immunology
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