scholarly journals The Anaphylatoxin C3a Receptor Expression on Human M2 Macrophages Is Down-Regulated by Stimulating the Histamine H4 Receptor and the IL-4 Receptor

2018 ◽  
Vol 10 (4) ◽  
pp. 349-362 ◽  
Author(s):  
Susanne Mommert ◽  
Derya Aslan ◽  
Lisanne Ratz ◽  
Holger Stark ◽  
Ralf Gutzmer ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Receptor Expression ◽  
M2 Macrophages ◽  
Histamine H4 Receptor ◽  
Th2 Cytokine ◽  
H4 Receptor ◽  
Differentiation Marker ◽  
Anaphylatoxin C3a ◽  
G Protein Coupled

The anaphylatoxin C3a triggers inflammation by binding to its specific G-protein-coupled C3a receptor (C3aR). Since the number of C3aR, which is expressed on the cell surface, affects the response to C3a, we investigated the expression levels of C3aR on human M2 macrophages in allergic situations where high levels of the Th2 cytokine IL-4 and histamine are present in a local microenvironment. The histamine H1 receptor (H1R), H2R and the H4R mRNA expressions were induced or up-regulated during the differentiation process of M2 macrophages. The presence of histamine or agonists targeting the H1R, H2R and, in particular, the H4R during in vitro differentiation from monocytes to macrophages modified the M2 phenotype by regulating the macrophage differentiation marker CD68 and CD163 expressions. In ­addition, the C3aR expression was also down-regulated by ­ST-1006 during this process. Histamine and ST-1006 down-regulated the expression of C3aR with different time kinetics on fully differentiated M2 macrophages. By analysing C3a-induced IL-6 mRNA expression, we observed a diminished response to C3a in ST-1006-treated M2 macrophages when compared to un-treated cells. Expression of C3 was not affected by histamine, whereas IL-4 strongly down-regulated C3aR and C3 expressions. Our data suggests that down-regulation of C3aR expression by mediators present in allergic situations such as IL-4 or histamine has an anti-inflammatory impact by reducing the sensitivity to C3a-induced down-stream signaling, thereby contributing to the regulation of local inflammatory responses in the skin.

scholarly journals The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis

2013 ◽  
Vol 73 (3) ◽  
pp. 600-608 ◽  
Author(s):  
Jeffery M Cowden ◽  
Fuqu Yu ◽  
Homayon Banie ◽  
Mandana Farahani ◽  
Ping Ling ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Inflammatory Responses ◽  
Total Production ◽  
Histamine H4 Receptor ◽  
Model Treatment ◽  
H4 Receptor ◽  
The Impact ◽  
Deficient Mice

ObjectiveThe histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.MethodsH4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.ResultsBoth H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.ConclusionsThese results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.

scholarly journals Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

Life ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 50
Author(s):  
Pakhuri Mehta ◽  
Przemysław Miszta ◽  
Przemysław Rzodkiewicz ◽  
Olga Michalak ◽  
Piotr Krzeczyński ◽  
...  
Keyword(s):  
Cell Activation ◽  
Histamine Receptor ◽  
Mast Cell Activation ◽  
Histamine H4 Receptor ◽  
Inflammatory Models ◽  
The Family ◽  
Cellular Pathways ◽  
H4 Receptor ◽  
G Protein Coupled

The histamine H4 receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H4R ligands are being studied for the treatment of several inflammatory, allergic, and autoimmune disorders, including pulmonary fibrosis. Activation of H4R is involved in cytokine production and mediates mast cell activation and eosinophil chemotaxis. The importance of this receptor has also been shown in inflammatory models: peritonitis, respiratory tract inflammation, colitis, osteoarthritis, and rheumatoid arthritis. Recent studies suggest that H4R acts as a modulator in cancer, neuropathic pain, vestibular disorders, and type-2 diabetes, however, its role is still not fully understood.

scholarly journals Reconstruction of integrin activation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 26-33 ◽  
Author(s):  
Feng Ye ◽  
Chungho Kim ◽  
Mark H. Ginsberg
Keyword(s):  
Plasma Membranes ◽  
Inflammatory Responses ◽  
Integrin Signaling ◽  
Lactose Permease ◽  
Cell Matrix ◽  
Mediate Cell ◽  
Signaling Receptors ◽  
The Moment ◽  
G Protein Coupled

Abstract Integrins are integral membrane proteins that mediate cell-matrix and cell-cell adhesion. They are important for vascular development and hematopoiesis, immune and inflammatory responses, and hemostasis. Integrins are also signaling receptors that can transmit information bidirectionally across plasma membranes. Research in the past 2 decades has made progress in unraveling the mechanisms of integrin signaling and brings the field to the moment of attempting synthetic reconstruction of the signaling pathways in vitro. Reconstruction of biologic processes provides stringent tests of our understanding of the process, as evidenced by studies of other biologic machines, such as ATP synthase, lactose permease, and G-protein–coupled receptors. Here, we review recent progress in reconstructing integrin signaling and the insights that we have gained through these experiments.

scholarly journals Histamine H4 Receptor Expression in Human Synovial Cells Obtained from Patients Suffering from Rheumatoid Arthritis

2005 ◽  
Vol 28 (10) ◽  
pp. 2016-2018 ◽  
Author(s):  
Yoshiko Ikawa ◽  
Masahiko Suzuki ◽  
Satoshi Shiono ◽  
Emi Ohki ◽  
Hideshige Moriya ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Receptor Expression ◽  
Synovial Cells ◽  
Histamine H4 Receptor ◽  
H4 Receptor

scholarly journals Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor

MedChemComm ◽  
2015 ◽  
Vol 6 (6) ◽  
pp. 1003-1017 ◽  
Author(s):  
Enade P. Istyastono ◽  
Albert J. Kooistra ◽  
Henry F. Vischer ◽  
Martien Kuijer ◽  
Luc Roumen ◽  
...  
Keyword(s):  
Virtual Screening ◽  
G Protein ◽  
Histamine H4 Receptor ◽  
H4 Receptor ◽  
G Protein Coupled ◽  
Homology Models

Structure-based virtual screening using H1R- and β2R-based histamine H4R homology models identified 9 fragments with an affinity ranging from 0.14 to 6.3 μm for H4R.

scholarly journals Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane hunter-horticulturalists

2021 ◽  
Author(s):  
India Schneider-Crease ◽  
Aaron D. Blackwell ◽  
Thomas S. Kraft ◽  
Melissa Emery Thompson ◽  
Ivan Maldonado Suarez ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Remote Communities ◽  
Necrosis Factor Alpha ◽  
H1n1 Vaccine ◽  
Gm Csf ◽  
Th2 Cytokine ◽  
Cytokine Responses ◽  
Macrophage Colony

AbstractBackgroundSoil-transmitted helminth (STH) infections can catalyze immunological changes that affect the response to subsequent infections, particularly those that elicit strong inflammatory responses. As globalization heightens the risk that remote communities with high STH prevalence will encounter novel pathogens, understanding how STHs shape immune responses to these downstream infections becomes increasingly crucial.MethodologyWe worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels—most likely indicative of infection in this population—are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (interferon gamma [INF-γ], interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, Granulocyte-macrophage colony-stimulating factor [GM-CSF], and Tumor necrosis factor-alpha [TNF-α]). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation.ResultsInfection with Ascaris lumbricoides was significantly (p ≤ 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men.Conclusions and implicationsWe find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens, and suggest that this mitigation of host-induced damage may reduce the incidence of cytokine storms in populations with high STH prevalence.

scholarly journals Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis

2019 ◽  
Vol 3 (1) ◽  
pp. e201900465 ◽  
Author(s):  
Robert Brenig ◽  
Oltin T Pop ◽  
Evangelos Triantafyllou ◽  
Anne Geng ◽  
Arjuna Singanayagam ◽  
...  
Keyword(s):  
Disease Severity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Infectious Complications ◽  
Receptor Expression ◽  
Tnf Α ◽  
Acute Decompensation

Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli. Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.

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