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1.
Front Immunol ; 9: 132, 2018.
Article in English | MEDLINE | ID: mdl-29445379

ABSTRACT

Influenza A virus (IAV) is recognized to cause severe pulmonary illnesses in humans, particularly in elderly and children. One of the features associated with IAV infection is an excessive lung inflammation due to an uncontrolled immune response. The nucleotide-binding oligomerization domain 2 (NOD2) receptor is known to recognize ssRNA viruses such as IAV, but its role in the inflammatory process during viral infections remains to be clarified. In a previous report, we have shown that activation of NOD2 with muramyl dipeptide (MDP) significantly reduces both viral loads and lung inflammation and also improves pulmonary function during IAV infection. These findings prompted us to further investigate whether NOD2 receptor may contribute to regulate inflammation during viral infection. In the present study, we show that administration of MDP to mice infected with IAV stimulates the migration of regulatory T (Treg) cells to the lungs. Such a presence of Treg cells was also accompanied with a reduction of neutrophils in the lungs during IAV infection, which correlated, with a significant decrease of Th17 cells. In our model, Treg cell recruitment is dependent of CXCL12 and CCL5 chemokines. Moreover, we show that the presence of Ly6Clow patrolling monocytes is required for Treg cells mobilization to the lung of mice treated with MDP. In fact, following monocyte depletion by administration of clodronate liposome, mobilization of Treg cells to the lungs of treated mice was found to occur when circulating Ly6Clow monocytes begin to reemerge. In addition, we also detected an increased production of TGF-ß, a cytokine contributing to Treg activity when blood Ly6Clow monocytes are restored. Together, our results demonstrate that MDP treatment can promote an anti-inflammatory environment through the mobilization of Treg cells to the lung, a mechanism that requires the presence of Ly6Clow monocytes during IAV infection. Overall, our results suggest that activation of NOD2 receptor could be an appealing approach to control pulmonary inflammation in patients infected with IAV.


Subject(s)
Nod2 Signaling Adaptor Protein/immunology , Orthomyxoviridae Infections/immunology , T-Lymphocytes, Regulatory/immunology , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Animals , Influenza A virus , Lung/drug effects , Lung/immunology , Mice, Inbred C57BL , Mice, Knockout , Monocytes/drug effects , Monocytes/immunology , Nod2 Signaling Adaptor Protein/agonists , Nod2 Signaling Adaptor Protein/genetics , T-Lymphocytes, Regulatory/drug effects
2.
Eur J Immunol ; 48(2): 250-257, 2018 02.
Article in English | MEDLINE | ID: mdl-28980305

ABSTRACT

Viruses, particularly the Epstein-Barr virus (EBV) has long been suspected to exacerbate acute arthritic symptoms. However, the cell populations that contribute to import viruses into the inflamed tissues remain to be identified. In the present study, we have investigated the role of monocytes in the transport of Murid herpesvirus 68 (MHV-68), a mouse virus closely related to EBV, using the serum transfer-induced arthritis (STIA) model. We found compelling evidence that MHV-68 infection markedly increased disease severity in NR4A1-/- mice, which are deficient for Ly6Clow monocytes. In contrast, the MHV-68-induced enhancement of joint inflammation was lessened in CCR2-/- mice, suggesting the involvement of inflammatory Ly6Chigh monocytes in viral transport. We also observed that following selective depletion of monocyte subsets by administration of clodronate, MHV-68 transport into the synovium occurs only in the presence of Ly6Chigh monocytes. Tracking of adoptively transferred Ly6Chigh GFP infected monocytes into arthritic CCR2-/- mice by two-photon intravital microscopy showed that this monocyte subset has the capacity to deliver viruses to inflamed AR joints, as confirmed by the detection of viral DNA in inflamed tissues of recipient mice. We thus conclude that Ly6Chigh monocytes import MHV-68 when they are mobilized to the inflamed arthritic joint.


Subject(s)
Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Epstein-Barr Virus Infections/immunology , Herpesviridae Infections/immunology , Herpesvirus 4, Human/physiology , Monocytes/immunology , Rhadinovirus/physiology , Tumor Virus Infections/immunology , Adoptive Transfer , Animals , Antigens, Ly/metabolism , Arthritis, Experimental/virology , Arthritis, Rheumatoid/virology , Cells, Cultured , DNA, Viral/analysis , Disease Models, Animal , Epstein-Barr Virus Infections/virology , Female , Herpesviridae Infections/virology , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/transplantation , Muridae , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Receptors, CCR2/genetics , Rhadinovirus/pathogenicity , Tumor Virus Infections/virology
3.
PLoS One ; 12(10): e0186639, 2017.
Article in English | MEDLINE | ID: mdl-29053748

ABSTRACT

The transcription factor NR4A1 has emerged as a pivotal regulator of the inflammatory response and immune homeostasis. Although contribution of NR4A1 in the innate immune response has been demonstrated, its role in host defense against viral infection remains to be investigated. In the present study, we show that administration of cytosporone B (Csn-B), a specific agonist of NR4A1, to mice infected with influenza virus (IAV) reduces lung viral loads and improves pulmonary function. Our results demonstrate that administration of Csn-B to naive mice leads to a modest production of type 1 IFN. However, in IAV-infected mice, such production of IFNs is markedly increased following treatment with Csn-B. Our study also reveals that alveolar macrophages (AMs) appear to have a significant role in Csn-B effects, since selective depletion of AMs with clodronate liposome correlates with a marked reduction of IFN production, viral clearance and morbidity in IAV-infected mice. Furthermore, when reemergence of AMs is observed following clodronate liposome administration, an increased production of IFNs was detected in bronchoalveolar fluids of IAV-infected mice treated with Csn-B, supporting the contribution of AMs in Csn-B effects. While treatment of mice with Csn-B induces phosphorylation of transcriptional factors IRF3 and IRF7, the latter appears to be less indispensable since effects of Csn-B treatment on the synthesis of IFNs were slightly affected in IAV-infected mice lacking functional IRF7. Together, our results highlight the capacity of Csn-B and consequently of NR4A1 transcription factor in controlling IAV infection.


Subject(s)
Influenza, Human/prevention & control , Lung/physiopathology , Nuclear Receptor Subfamily 4, Group A, Member 1/agonists , Phenylacetates/pharmacology , Animals , Female , Humans , Influenza, Human/physiopathology , Interferon Type I/biosynthesis , Mice , Mice, Inbred C57BL , Respiratory Function Tests , Viral Load
4.
Cell Rep ; 20(8): 1830-1843, 2017 Aug 22.
Article in English | MEDLINE | ID: mdl-28834747

ABSTRACT

The signals that regulate the fate of circulating monocytes remain unknown. In the present study, we demonstrate that triggering of the NOD2 receptor by muramyl dipeptide (MDP) converts inflammatory Ly6Chigh monocytes into patrolling Ly6Clow monocytes. Administration of MDP to Nr4a1-/- mice, which lack Ly6Clow monocytes, or to Ly6Clow-depleted mice led to the emergence of blood-patrolling monocytes with a profile similar to that of Ly6Clow monocytes, including high expression of CX3CR1 and LFA1. Using intravital microscopy in animal models of inflammatory diseases, we also found that converted Ly6Chigh monocytes patrol the endothelium of blood vessels and that their presence contributes to a reduction in the inflammatory response following MDP injection. Our results demonstrate that NOD2 contributes to the regulation of blood monocytes and suggest that it could be therapeutically targeted to treat inflammatory diseases.


Subject(s)
Antigens, Ly/immunology , Monocytes/immunology , Nod2 Signaling Adaptor Protein/immunology , Animals , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nod2 Signaling Adaptor Protein/genetics
5.
Eur J Immunol ; 46(12): 2789-2800, 2016 12.
Article in English | MEDLINE | ID: mdl-27600773

ABSTRACT

Monocytes are central to the physiopathology of arthritis, but their roles in progression and resolution of the disease remain to be clarified. Using NR4A1-/- mice, which lack patrolling lymphocyte antigen 6C (Ly6Clow ) monocytes, we found that inflammatory Ly6Chigh monocytes contribute to rapid development of arthritis in a serum transfer-induced arthritis (STIA) model. Our experiments suggest that patrolling monocytes do not promote the initiation and progression of arthritis in mice, as severity of symptoms was amplified in NR4A1-/- mice. Moreover, we show that treatment of arthritic wild type (WT) mice with cytosporone B (Csn-B), a NR4A1-specific agonist, significantly reduces severity of disease. Effects of Csn-B were absent in monocyte-depleted mice treated with clodronate until Ly6Clow monocytes were restored. Adoptive transfer of Ly6Clow monocytes in arthritic NR4A1-/- mice treated with Csn-B reduces joint inflammation, supporting the regulatory role of Ly6Clow subset on disease development. Our results also reveal that administration of Csn-B to arthritic mice enhances levels of circulating CD4+ CD25+ FoxP3+ Treg cells, a process requiring the presence of Ly6Clow monocytes. Together, these data indicate that Ly6Chigh monocytes are involved in the initiation and progression of arthritis and Ly6Clow monocytes contribute to reduce joint inflammation through the mobilization of Treg cells.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis/immunology , Inflammation/immunology , Joints/immunology , Monocytes/immunology , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , Antigens, Ly/metabolism , Arthritis/drug therapy , Cells, Cultured , Disease Models, Animal , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Phenylacetates/therapeutic use
6.
Arthritis Res Ther ; 18: 10, 2016 Jan 13.
Article in English | MEDLINE | ID: mdl-26759164

ABSTRACT

BACKGROUND: Synovial infiltration of monocytes is commonly associated with inflammation in rheumatoid arthritis (RA). Toll-like receptors (TLRs) are innate sensors that recognize cell debris and microbial components in host, a process contributing to maintain chronic inflammation in RA. We assessed the expression levels of TLR2 and TLR9 in monocyte subsets of active RA patients and characterized their cytokine profiles in response to synthetic and viral TLR2 and TLR9 agonists, including Epstein-Barr virus (EBV) which is suspected to contribute to RA symptoms. METHODS: Prevalence of monocyte subsets CD14(++) CD16(-), CD14(+) CD16(+) and CD14(low) CD16(++) was evaluated in blood and synovial fluids of active RA patients and levels of TLR2 and TLR9 in monocyte subsets were measured by flow cytometry. Enriched monocytes derived from RA patients and healthy donors were stimulated in vitro with synthetic TLR2 and TLR9 agonists and with EBV particles or viral DNA. Intracellular cytokine profiles were determined in respective monocyte subsets. Finally, the presence of EBV genome was evaluated by real-time PCR in blood and synovial monocytes of RA patients. RESULTS: Numbers of CD14(+) CD16(+) and CD14(low) CD16(++) were found to increase in blood of RA patients compared to healthy controls, while all three subsets were detected in synovial fluids. TLR2 is abundantly expressed on blood and synovial CD14(++) CD16(-) and CD14(+) CD16(+) monocytes from RA patients. Levels of TLR9 were increased on all three subsets of blood monocytes but markedly enhanced in monocytes isolated from synovial fluids. Compared to healthy controls, CD14(++) CD16(-) monocytes of RA patients displayed an enlarged capacity to produce proinflammatory cytokines after stimulation with synthetic TLR2 and TLR9 agonists while both CD14(++) CD16(-) and CD14(+) CD16(+) monocytes showed increased response to EBV stimulation. The presence of EBV genome was also detected in monocytes and neutrophils of a significant proportion of patients. CONCLUSION: Patients with active RA show an increased expression of TLR2 and TLR9 on monocyte subsets and display higher production of inflammatory cytokines in response to TLR agonists. The presence of EBV genome in monocytes and neutrophils reinforces the suspected role of the virus in the exacerbation of RA symptoms.


Subject(s)
Arthritis, Rheumatoid/metabolism , Monocytes/metabolism , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/biosynthesis , Toll-Like Receptor 9/agonists , Toll-Like Receptor 9/biosynthesis , Aged , Female , Flow Cytometry/methods , Gene Expression Regulation , Humans , Inflammation Mediators/metabolism , Lipopolysaccharides/pharmacology , Male , Middle Aged , Monocytes/drug effects , Teichoic Acids/pharmacology , Treatment Outcome
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