Triggering of NOD2 Receptor Converts Inflammatory Ly6C high into Ly6C low Monocytes with Patrolling Properties

Lessard, Anne-Julie; Lebel, Manon; Egarnes, Benoit; Préfontaine, Paul; Thériault, Peter; Droit, Arnaud; Brunet, A. Gómez; Rivest, Serge; Gosselin, Jean

doi:10.1016/j.celrep.2017.08.009

Cited by 61 publications

(76 citation statements)

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“…We also confirmed that treatment of infected mice with MDP markedly increases the presence of Tregs to the lungs of mice (Figures 6 B,C). This is consistent with our previous report showing that MDP treatment induces the conversion of blood Ly6C high monocytes into Ly6C low monocytes and consequently their number in the circulation ( 52 ). Presence of Tregs in lungs of mice also coincides with the optimal production of CXCL12, CCL5 and TGF-β in lungs of IAV-infected mice treated with MDP compared to mice treated with a placebo (Figures 6 D–F).…”

Section: Resultssupporting

confidence: 94%

“…We have previously reported that Ly6C low patrolling monocytes are important for trafficking of Treg cells in a mouse model of arthritis and that in vivo administration of MDP increases levels of Ly6C low monocytes in the blood of mice ( 51 , 52 ). We wanted to determine whether Ly6C low monocytes are essential to Treg recruitment in lung of mice during IAV infection.…”

Section: Resultsmentioning

confidence: 99%

“…In naive and IAV-infected mice treated with placebo, we observed that Ly6C low patrolling monocytes gradually remerge at day 6 postclodronate and are fully restored by day 8 (Figure 5 B). However, a more rapid emergence of Ly6C low patrolling monocytes was observed following MDP treatment, starting to re-emerged at day 4 postclodronate administration due to the conversion of Ly6C high into Ly6C low monocytes following NOD2 triggering ( 52 ).…”

Section: Resultsmentioning

confidence: 99%

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Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Egarnes

Gosselin

2018

Front. Immunol.

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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-β, 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.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Egarnes

Gosselin

2018

Front. Immunol.

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“…Thus, our data suggest a redundancy between Ly6C low and Ly6C high monocytes for the endothelial repair process. Recently, it was shown that Ly6C high monocytes can be converted into Ly6C low monocytes with endothelial patrolling properties . Such a conversion may explain why neither monocyte subtype (Ly6C high or Ly6C low ) is solely required for the endothelial repair process.…”

Section: Discussionmentioning

confidence: 99%

Endothelial repair is dependent on CD11c+ leukocytes to establish regrowing endothelial sheets with high cellular density

Holm

Levin

Alsén

et al. 2018

Journal of Leukocyte Biology

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Endothelial injury makes the vessel wall vulnerable to cardiovascular diseases. Injured endothelium regenerates by collective sheet migration, that is, the endothelial cells coordinate their motion and regrow as a sheet of cells with retained cell-cell contacts into the wounded area.Leukocytes appear to be involved in endothelial repair in vivo; however, little is known about their identity and role in the reparative sheet migration process. To address these questions, we developed a high-quality en face technique that enables visualizing of leukocytes and endothelial cells simultaneously following an endoluminal scratch wound injury of the mouse carotid artery. We discovered that regrowing endothelium forms a broad proliferative front accompanied by CD11c + leukocytes. Functionally, the leukocytes were dispensable for the initial migratory response of the regrowing endothelial sheet, but critical for the subsequent formation and maintenance of a front zone with high cellular density. Marker expression analyses, genetic fate mapping, phagocyte targeting experiments, and mouse knock-out experiments indicate that the CD11c + leukocytes were mononuclear phagocytes with an origin from both Ly6C high and Ly6C low monocytes. In conclusion, CD11c + mononuclear phagocytes are essential for a proper endothelial regrowth following arterial endoluminal scratch injury. Promoting the endothelial-preserving function of CD11c + leukocytes may be a strategy to enhance endothelial repair following surgical and endovascular procedures.

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“…Similar activation results upon MDP treatment were also observed in human DCs differentiated in vitro using mononuclear bone marrow cells purified from acute leukaemia patients. 140 More broadly, MDP was shown to elicit the migration of Ly6C high monocytes from the bone marrow to the lungs 141 and to convert inflammatory, Ly6C high monocytes into Ly6C low monocytes that exhibit patrolling properties, 142 highlighting the complex and likely simultaneous activities of MDP in systemic circulation on myeloid cell populations.…”

Section: Peptidoglycan Metabolites and Cancer Treatmentmentioning

confidence: 99%

Translation of peptidoglycan metabolites into immunotherapeutics

et al. 2019

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The discovery of defined peptidoglycan metabolites that activate host immunity and their specific receptors has revealed fundamental insights into host–microbe recognition and afforded new opportunities for therapeutic development against infection and cancer. In this review, we summarise the discovery of two key peptidoglycan metabolites, γ‐d‐glutamyl‐meso‐diaminopimelic acid (iE‐DAP) and muramyl dipeptide and their respective receptors, Nod1 and Nod2, and review progress towards translating these findings into therapeutic agents. Notably, synthetic derivatives of peptidoglycan metabolites have already yielded approved drugs for chemotherapy‐induced leukopenia and paediatric osteosarcoma; however, the broad effects of peptidoglycan metabolites on host immunity suggest additional translational opportunities for new therapeutics towards other cancers, microbial infections and inflammatory diseases.

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Triggering of NOD2 Receptor Converts Inflammatory Ly6C high into Ly6C low Monocytes with Patrolling Properties

Cited by 61 publications

References 50 publications

Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection

Endothelial repair is dependent on CD11c+ leukocytes to establish regrowing endothelial sheets with high cellular density

Translation of peptidoglycan metabolites into immunotherapeutics

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