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1.
Immunol Rev ; 313(1): 339-357, 2023 01.
Article in English | MEDLINE | ID: mdl-36217774

ABSTRACT

Dysregulation of the alternative complement pathway predisposes individuals to a number of diseases. It can either be evoked by genetic alterations in or by stabilizing antibodies to important pathway components and typically leads to severe diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. In addition, the alternative pathway may also be involved in many other diseases where its amplifying function for all complement pathways might play a role. To identify specific alternative pathway inhibitors that qualify as therapeutics for these diseases, drug discovery efforts have focused on the two central proteases of the pathway, factor B and factor D. Although drug discovery has been challenging for a number of reasons, potent and selective low-molecular weight (LMW) oral inhibitors have now been discovered for both proteases and several molecules are in clinical development for multiple complement-mediated diseases. While the clinical development of these inhibitors initially focuses on diseases with systemic and/or peripheral tissue complement activation, the availability of LMW inhibitors may also open up the prospect of inhibiting complement in the central nervous system where its activation may also play an important role in several neurodegenerative diseases.


Subject(s)
Atypical Hemolytic Uremic Syndrome , Complement Pathway, Alternative , Humans , Molecular Weight , Complement System Proteins/metabolism , Complement Activation , Complement Factor D/metabolism , Atypical Hemolytic Uremic Syndrome/metabolism
2.
Immunity ; 43(5): 998-1010, 2015 Nov 17.
Article in English | MEDLINE | ID: mdl-26522986

ABSTRACT

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.


Subject(s)
Gastrointestinal Microbiome/immunology , Helminths/immunology , Hypersensitivity/immunology , Inflammation/immunology , Inflammation/parasitology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Adult , Aged , Animals , Asthma/immunology , Asthma/microbiology , Asthma/parasitology , Cytokines/immunology , Fatty Acids/immunology , Female , Humans , Hypersensitivity/microbiology , Hypersensitivity/parasitology , Inflammation/microbiology , Intestinal Mucosa/parasitology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Nematospiroides dubius/immunology , Receptors, G-Protein-Coupled/immunology , Strongylida Infections/immunology , Strongylida Infections/microbiology , Strongylida Infections/parasitology
3.
J Immunol ; 203(11): 2791-2806, 2019 12 01.
Article in English | MEDLINE | ID: mdl-31659015

ABSTRACT

The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and MALT1 mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4+ T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ-producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in MALT1.


Subject(s)
Autoimmunity/immunology , Homeostasis/immunology , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Mice , Mice, Inbred C57BL , Mice, Knockout , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/deficiency , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/genetics
4.
Nat Immunol ; 9(6): 667-75, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18425132

ABSTRACT

The generation of lymphoid microenvironments in early life depends on the interaction of lymphoid tissue-inducer cells with stromal lymphoid tissue-organizer cells. Whether this cellular interface stays operational in adult secondary lymphoid organs has remained elusive. We show here that during acute infection with lymphocytic choriomeningitis virus, antiviral cytotoxic T cells destroyed infected T cell zone stromal cells, which led to profound disruption of secondary lymphoid organ integrity. Furthermore, the ability of the host to respond to secondary antigens was lost. Restoration of the lymphoid microanatomy was dependent on the proliferative accumulation of lymphoid tissue-inducer cells in secondary lymphoid organs during the acute phase of infection and lymphotoxin alpha(1)beta(2) signaling. Thus, crosstalk between lymphoid tissue-inducer cells and stromal cells is reactivated in adults to maintain secondary lymphoid organ integrity and thereby contributes to the preservation of immunocompetence.


Subject(s)
Arenaviridae Infections/immunology , Lymphatic System/physiology , Lymphocytic choriomeningitis virus/immunology , Stromal Cells/metabolism , T-Lymphocytes, Cytotoxic/immunology , Animals , Arenaviridae Infections/blood , Arenaviridae Infections/virology , Lymphocyte Activation/immunology , Lymphoid Tissue/immunology , Organ Specificity , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Helper-Inducer
5.
Nat Immunol ; 9(11): 1261-9, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18820681

ABSTRACT

Succinate acts as an extracellular mediator signaling through the G protein-coupled receptor GPR91. Here we show that dendritic cells had high expression of GPR91. In these cells, succinate triggered intracellular calcium mobilization, induced migratory responses and acted in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines. Succinate also enhanced antigen-specific activation of human and mouse helper T cells. GPR91-deficient mice had less migration of Langerhans cells to draining lymph nodes and impaired tetanus toxoid-specific recall T cell responses. Furthermore, GPR91-deficient allografts elicited weaker transplant rejection than did the corresponding grafts from wild-type mice. Our results suggest that the succinate receptor GPR91 is involved in sensing immunological danger, which establishes a link between immunity and a metabolite of cellular respiration.


Subject(s)
Dendritic Cells/immunology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/immunology , Succinic Acid/metabolism , T-Lymphocytes/immunology , Animals , Cell Line, Tumor , Cell Movement , Cytokines/biosynthesis , Dendritic Cells/metabolism , Graft Rejection/immunology , Humans , Langerhans Cells/cytology , Lymph Nodes/immunology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, SCID , Receptors, Antigen, T-Cell/agonists , Receptors, Antigen, T-Cell/antagonists & inhibitors , Receptors, Antigen, T-Cell/immunology , Receptors, G-Protein-Coupled/genetics , Signal Transduction/immunology , Succinic Acid/pharmacology , T-Lymphocytes, Helper-Inducer/immunology , Up-Regulation
6.
Nat Immunol ; 9(3): 282-91, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18204450

ABSTRACT

After homing to lymph nodes, CD8+ T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell-DC interactions. We show here that the duration of phase one and T cell activation kinetics correlated inversely with the number of complexes of cognate peptide and major histocompatibility complex (pMHC) per DC and with the density of antigen-presenting DCs per lymph node. Very few pMHC complexes were necessary for the induction of full-fledged T cell activation and effector differentiation. However, neither T cell activation nor transition to phase two occurred below a threshold antigen dose determined in part by pMHC stability. Thus, phase one permits T cells to make integrated 'measurements' of antigen dose that determine subsequent T cell participation in immune responses.


Subject(s)
Antigens, Surface/metabolism , Dendritic Cells/immunology , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Animals , Antigen-Presenting Cells/immunology , Antigens, Surface/genetics , Cells, Cultured , Dendritic Cells/metabolism , Dose-Response Relationship, Immunologic , Kinetics , Major Histocompatibility Complex/immunology , Male , Mice , Mice, Inbred C57BL , Peptide Fragments/genetics , T-Lymphocytes/metabolism
7.
Allergy ; 75(8): 1966-1978, 2020 08.
Article in English | MEDLINE | ID: mdl-32112426

ABSTRACT

BACKGROUND: Short-chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health, and suppress mast cell-mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs (acetate, propionate, and butyrate) on mast cell-mediated pathology and human mast cell activation, including the molecular mechanisms involved. METHOD: Precision-cut lung slices (PCLS) of allergen-exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co-cultured with SCFAs and assessed for degranulation after IgE- or non-IgE-mediated stimulation. The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays. RESULTS: Butyrate treatment inhibited allergen-induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE- and non-IgE-mediated human or mouse mast cell degranulation in a concentration-dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43, or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate-induced downregulation of the tyrosine kinases BTK, SYK, and LAT, critical transducers of FcεRI-mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK, and LAT promoter regions. CONCLUSION: Known health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation.


Subject(s)
Butyrates , Mast Cells , Animals , Butyrates/pharmacology , Cell Degranulation , Epigenesis, Genetic , Guinea Pigs , Humans , Mast Cells/metabolism , Mice , Protein-Tyrosine Kinases/metabolism , Receptors, IgE/genetics
8.
Bioorg Med Chem Lett ; 30(17): 127366, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32738975

ABSTRACT

Antagonism of the Toll-like receptors (TLRs) 7 and TLR8 has been hypothesized to be beneficial to patients suffering from autoimmune conditions. A phenotypic screen for small molecule antagonists of TLR7/8 was carried out in a murine P4H1 cell line. Compound 1 was identified as a hit that showed antagonistic activity on TLR7 and TLR8 but not TLR9, as shown on human peripheral blood mononuclear cells (hPBMCs). It was functionally cross reactive with mouse TLR7 but lacked oral exposure and had only modest potency. Chemical optimization resulted in 2, which showed in vivo efficacy following intraperitoneal administration. Further optimization resulted in 8 which had excellent in vitro activity, exposure and in vivo activity. Additional work to improve physical properties resulted in 15, an advanced lead that had favorable in vitro and exposure properties. It was further demonstrated that activity of the series tracked with binding to the extracellular domain of TLR7 implicating that the target of this series are endosomal TLRs rather than downstream signaling pathways.


Subject(s)
Piperazine/chemistry , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/metabolism , Administration, Oral , Animals , Cell Line , Drug Evaluation, Preclinical , Half-Life , Humans , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Male , Mice , Mice, Inbred BALB C , Piperazine/administration & dosage , Piperazine/pharmacokinetics , Piperazine/pharmacology , Spleen/cytology , Spleen/drug effects , Spleen/metabolism , Structure-Activity Relationship , Toll-Like Receptor 7/antagonists & inhibitors , Toll-Like Receptor 8/antagonists & inhibitors
9.
Nature ; 515(7525): 130-3, 2014 Nov 06.
Article in English | MEDLINE | ID: mdl-25337873

ABSTRACT

Secretion of C-C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. Here we report a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin (IL)-6- and vascular endothelial growth factor (VEGF)-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target. However, our results call for caution when considering anti-CCL2 agents as monotherapy in metastatic disease and highlight the tumour microenvironment as a critical determinant of successful anti-metastatic therapy.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Chemokine CCL2/antagonists & inhibitors , Chemokine CCL2/metabolism , Neoplasm Metastasis , Neovascularization, Pathologic , Animals , Blood Vessels/cytology , Blood Vessels/drug effects , Blood Vessels/growth & development , Cell Proliferation/drug effects , Disease Models, Animal , Female , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Lung Neoplasms/blood supply , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , Monocytes/cytology , Monocytes/metabolism , Neoplasm Metastasis/drug therapy , Neovascularization, Pathologic/drug therapy , Survival Analysis , Tumor Microenvironment , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism
10.
Blood ; 125(20): 3183-92, 2015 May 14.
Article in English | MEDLINE | ID: mdl-25814531

ABSTRACT

Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced interferon-γ production by st2(-/-) vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy.


Subject(s)
Graft vs Host Disease/immunology , Graft vs Host Disease/metabolism , Interleukins/metabolism , Receptors, Cell Surface/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Acute Disease , Animals , Cluster Analysis , Disease Models, Animal , Gene Expression , Gene Expression Profiling , Graft vs Host Disease/diagnosis , Graft vs Host Disease/genetics , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Interferon-gamma/biosynthesis , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33 , Interleukins/genetics , Intestinal Mucosa/metabolism , Intestines/pathology , Intestines/radiation effects , Isoantigens/immunology , Mice , Mice, Knockout , Receptors, Cell Surface/genetics , Severity of Illness Index , Tissue Donors , Transplantation Conditioning , Transplantation, Homologous
11.
Nature ; 465(7301): 1079-83, 2010 Jun 24.
Article in English | MEDLINE | ID: mdl-20577213

ABSTRACT

Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7-10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.


Subject(s)
Central Nervous System/immunology , Central Nervous System/virology , Lymph Nodes/immunology , Lymph Nodes/virology , Macrophages/immunology , Rhabdoviridae Infections/immunology , Vesiculovirus/immunology , Animals , Central Nervous System/cytology , Dendritic Cells/immunology , Injections , Interferon Type I/immunology , Lymph Nodes/cytology , Lymph Nodes/innervation , Macrophages/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Paralysis/complications , Paralysis/virology , Peripheral Nerves/virology , Receptor, Interferon alpha-beta/deficiency , Rhabdoviridae Infections/complications , Rhabdoviridae Infections/virology , Survival Rate , Vesicular stomatitis Indiana virus/immunology , Vesicular stomatitis Indiana virus/pathogenicity , Vesicular stomatitis Indiana virus/physiology , Vesicular stomatitis New Jersey virus/immunology , Vesicular stomatitis New Jersey virus/pathogenicity , Vesicular stomatitis New Jersey virus/physiology , Vesiculovirus/pathogenicity , Vesiculovirus/physiology
12.
Blood ; 121(20): 4101-9, 2013 May 16.
Article in English | MEDLINE | ID: mdl-23558016

ABSTRACT

It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not α4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute.


Subject(s)
B-Lymphocytes/physiology , Cell Communication/physiology , Chemokines/physiology , Chemotaxis, Leukocyte/genetics , Lymphocyte Function-Associated Antigen-1/metabolism , Receptors, CCR7/physiology , Receptors, CXCR4/physiology , Receptors, CXCR5/physiology , Stromal Cells/physiology , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/physiology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Cell Communication/drug effects , Chemokines/metabolism , Chemokines/pharmacology , Chemotaxis, Leukocyte/drug effects , Female , Gene Deletion , Lymphocyte Function-Associated Antigen-1/physiology , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, CCR7/genetics , Receptors, CCR7/metabolism , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Receptors, CXCR5/genetics , Receptors, CXCR5/metabolism , Stromal Cells/metabolism
13.
Gut ; 62(12): 1714-23, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23172891

ABSTRACT

OBJECTIVE: Inflammatory bowel diseases (IBD) have been intrinsically linked to a deregulated cytokine network, but novel therapeutic principles are urgently needed. Here we identify the interleukin (IL)-33 and its receptor ST2 as key negative regulators of wound healing and permeability in the colon of mice. DESIGN: Expression of IL-33 and ST2 was determined by qRT-PCR, ELISA, immunohistochemistry and western-blot analysis. Wild-type and St2(-/-) mice were used in wound healing experiments and in two experimental models of IBD triggered by 2,4,6-trinitrobenzene sulphonic acid or dextran sodium sulphate (DSS). Neutralisation of ST2 was performed by using a specific blocking antibody. RESULTS: Nuclear localisation and enhanced expression of IL-33 in myofibroblasts and enterocytes was linked to disease involvement independently of inflammation, while the expression of ST2 was primarily restricted to the colonic epithelia. In two experimental models of IBD, genetic ablation of ST2 significantly improved signs of colitis, while a sustained epithelial expression of the cyto-protective factor connexin-43 was observed in DSS-treated St2-deficient mice. Unexpectedly, absence of ST2 in non-hematopoietic cells was sufficient to protect against colitis. Consistently, specific inhibition of endogenous ST2-mediated signalling by treatment with neutralising antibody improved DSS-induced colitis. In addition, IL-33 treatment impaired epithelial barrier permeability in vitro and in vivo, whereas absence of ST2 enhanced wound healing response upon acute mechanical injury in the colon. CONCLUSIONS: Our study unveiled a novel non-hematopoietic function of IL-33 in epithelial barrier function and wound healing. Therefore, blocking the IL-33/ST2 axis may represent an efficient therapy in IBD.


Subject(s)
Colitis, Ulcerative/etiology , Interleukins/physiology , Receptors, Interleukin/physiology , Animals , Blotting, Western , Caco-2 Cells , Colitis, Ulcerative/physiopathology , Colitis, Ulcerative/therapy , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Humans , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33 , Intestinal Mucosa/metabolism , Male , Mice , Mice, Inbred C57BL , Permeability , Real-Time Polymerase Chain Reaction , Wound Healing/physiology
14.
J Invest Dermatol ; 144(7): 1544-1556.e9, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38237730

ABSTRACT

Atopic dermatitis (AD) is a debilitating inflammatory skin disorder. Biologics targeting the IL-4/IL-13 axis are effective in AD, but there is still a large proportion of patients who do not respond to IL-4R blockade. Further exploration of potentially pathogenic T-cell-derived cytokines in AD may lead to new effective treatments. This study aimed to investigate the downstream effects of IL-26 on skin in the context of type 2 skin inflammation. We found that IL-26 alone exhibited limited inflammatory activity in the skin. However, in the presence of IL-1ß, IL-26 potentiated the secretion of TSLP, CXCL1, and CCL20 from human epidermis through Jak/signal transducer and activator of transcription signaling. Moreover, in an in vivo AD-like skin inflammation model, IL-26 exacerbated skin pathology and locally increased type 2 cytokines, most notably of IL13 in skin T helper cells. Neutralization of IL-1ß abrogated IL-26-mediated effects, indicating that the presence of IL-1ß is required for full IL-26 downstream action in vivo. These findings suggest that the presence of IL-1ß enables IL-26 to be a key amplifier of inflammation in the skin. As such, IL-26 may contribute to the development and pathogenesis of inflammatory skin disorders such as AD.


Subject(s)
Dermatitis, Atopic , Interleukin-1beta , Interleukins , Humans , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Interleukin-1beta/metabolism , Animals , Mice , Interleukins/metabolism , Interleukins/immunology , Disease Models, Animal , Cytokines/metabolism , Signal Transduction/immunology , Female , Keratinocytes/immunology , Keratinocytes/metabolism , Skin/pathology , Skin/immunology , Cells, Cultured
15.
J Immunol ; 186(4): 2602-12, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21217016

ABSTRACT

The mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti-IL-17 therapy in collagen-induced arthritis ameliorates bone damage by reducing the number of osteoclasts in joints. We found equal numbers of CD4(+) Th17 and IL-17 producing γδ T cells in the joints of arthritic mice, and in vitro, both populations similarly induced osteoclastogenesis. However, individual depletion and adoptive transfer studies revealed that in vivo, Th17 cells dominated with regard to bone destruction. Unlike γδ T cells, Th17 cells were found in apposition to tartrate-resistant acid phosphatase positive osteoclasts in subchondral areas of inflamed joints, a pattern reproduced in patient biopsies. This localization was caused by Ag-specific retention, because OVA-primed Th17 cells showed a γδ T cell-like diffuse distribution. Because IL-23, as produced by osteoclasts, enhanced T cell-mediated osteoclastogenesis, we propose that Ag-specific juxtaposition is key to foster the molecular cross talk of Th17 cells and osteoclasts, thus driving arthritic bone destruction.


Subject(s)
Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Interleukin-17/biosynthesis , Receptors, Antigen, T-Cell, gamma-delta/biosynthesis , Th17 Cells/immunology , Th17 Cells/pathology , Adult , Aged , Animals , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Cartilage, Articular/immunology , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Cell Communication/immunology , Cell Differentiation/genetics , Cell Differentiation/immunology , Coculture Techniques , Collagen Type II/administration & dosage , Collagen Type II/immunology , Female , Humans , Interleukin-17/metabolism , Male , Mice , Mice, Inbred DBA , Middle Aged , Osteoclasts/immunology , Osteoclasts/metabolism , Osteoclasts/pathology , Th17 Cells/metabolism
16.
Nature ; 450(7166): 110-4, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17934446

ABSTRACT

Lymph nodes prevent the systemic dissemination of pathogens such as viruses that infect peripheral tissues after penetrating the body's surface barriers. They are also the staging ground of adaptive immune responses to pathogen-derived antigens. It is unclear how virus particles are cleared from afferent lymph and presented to cognate B cells to induce antibody responses. Here we identify a population of CD11b+CD169+MHCII+ macrophages on the floor of the subcapsular sinus (SCS) and in the medulla of lymph nodes that capture viral particles within minutes after subcutaneous injection. Macrophages in the SCS translocated surface-bound viral particles across the SCS floor and presented them to migrating B cells in the underlying follicles. Selective depletion of these macrophages compromised local viral retention, exacerbated viraemia of the host, and impaired local B-cell activation. These findings indicate that CD169+ macrophages have a dual physiological function. They act as innate 'flypaper' by preventing the systemic spread of lymph-borne pathogens and as critical gatekeepers at the lymph-tissue interface that facilitate the recognition of particulate antigens by B cells and initiate humoral immune responses.


Subject(s)
B-Lymphocytes/immunology , Lymph Nodes/immunology , Lymph Nodes/virology , Lymph/virology , Macrophages/immunology , Vesiculovirus/immunology , Animals , Antibody Formation/immunology , CD11b Antigen/metabolism , Cell Line , Lymph Nodes/cytology , Macrophages/metabolism , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Receptors, Immunologic/metabolism , Sialic Acid Binding Ig-like Lectin 1
17.
J Mammary Gland Biol Neoplasia ; 17(2): 125-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22581273

ABSTRACT

A fundamental hallmark of cancer is progression to metastasis and the growth of breast cancer metastases in lung, bone, liver and/or brain causes fatal complications. Unfortunately, the cellular and biochemical mechanisms of the metastatic process remain ill-defined. Recent application of intravital multiphoton microscopy (MP-IVM) to image fluorescently labeled cells in mouse models of cancer has allowed dynamic observation of this multi-step process at the cellular and subcellular levels. In this article, we discuss the use of MP-IVM in studies of breast cancer metastasis, as well as surgical techniques for exposing tumors prior to imaging. We also describe a versatile multiphoton microscope for imaging tumor-stroma interactions.


Subject(s)
Breast Neoplasms/pathology , Green Fluorescent Proteins/metabolism , Lymphatic Metastasis/pathology , Mammary Glands, Animal/pathology , Neoplasm Proteins/metabolism , Animals , Bone Marrow Neoplasms/pathology , Bone Marrow Neoplasms/secondary , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Fluorescence Resonance Energy Transfer , Green Fluorescent Proteins/genetics , Immunocompromised Host , Mammary Glands, Animal/metabolism , Mice , Mice, Transgenic , Microscopy, Fluorescence, Multiphoton/instrumentation , Neoplasm Proteins/genetics , Neoplasm Transplantation/pathology , Stromal Cells/metabolism , Stromal Cells/pathology
18.
Eur J Drug Metab Pharmacokinet ; 48(5): 553-566, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37532923

ABSTRACT

BACKGROUND AND OBJECTIVE: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370. METHODS: This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated. RESULTS: MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.). CONCLUSION: The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.


Subject(s)
Toll-Like Receptor 7 , Toll-Like Receptor 8 , Humans , Adult , Animals , Mice , Area Under Curve , Fasting , Administration, Oral , Double-Blind Method , Dose-Response Relationship, Drug , Healthy Volunteers
19.
ACS Med Chem Lett ; 14(8): 1054-1062, 2023 Aug 10.
Article in English | MEDLINE | ID: mdl-37583811

ABSTRACT

Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease.

20.
Cell Rep Med ; 4(5): 101036, 2023 05 16.
Article in English | MEDLINE | ID: mdl-37196635

ABSTRACT

Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cytokines in human and mouse cells, notably interferon-α, a clinically validated driver of autoimmune diseases. Moreover, MHV370 abrogates B cell, plasmacytoid dendritic cell, monocyte, and neutrophil responses downstream of TLR7/8. In vivo, prophylactic or therapeutic administration of MHV370 blocks secretion of TLR7 responses, including cytokine secretion, B cell activation, and gene expression of, e.g., interferon-stimulated genes. In the NZB/W F1 mouse model of lupus, MHV370 halts disease. Unlike hydroxychloroquine, MHV370 potently blocks interferon responses triggered by specific immune complexes from systemic lupus erythematosus patient sera, suggesting differentiation from clinical standard of care. These data support advancement of MHV370 to an ongoing phase 2 clinical trial.


Subject(s)
Autoimmune Diseases , Lupus Erythematosus, Systemic , Humans , Mice , Animals , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 7/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/metabolism , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Interferons
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