Triggering of NOD2 Receptor Converts Inflammatory Ly6Chigh into Ly6Clow Monocytes with Patrolling Properties

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

doi:10.1016/j.celrep.2017.08.009

Anne-Julie Lessard, Manon Lebel + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2017.08.009

Copy DOI

Journal: Cell Reports	Publication Date: Aug 1, 2017
Citations: 52	License type: cc-by

Affiliation: Université Laval

Abstract

The signals that regulate the fate of circulating monocytes remain unknown. In the present study, we demonstrate that triggering of the NOD2 receptor bymuramyl 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.

Highlights

NOD2 receptor, a member of the NOD-like receptor family, is recognized as a cytosolic protein that responds to fragments of bacterial peptidoglycan such as muramyl dipeptide (MDP) to activate innate immunity to bacterial infection (Girardin et al, 2003a; Grimes et al, 2012; Inohara et al, 2000; Ogura et al, 2001)
Because NOD2 was suspected to play a role in inflammation, we wanted first to evaluate the effects of NOD2 triggering on monocyte subsets
Intravenous (i.v.) administration of NOD2 agonist MDP to wild-type (WT) mice significantly increases the level of blood monocytes after 2 days of treatment to reach almost a 1.5-fold increase after 96 hr of stimulation, suggesting that MDP treatment might stimulate the exit of monocytes from the bone marrow (BM) (Figure 1A)

Summary

Graphical Abstract

The signals that regulate the conversion of inflammatory monocytes into patrolling subset(s) remain unknown. Lessard et al demonstrate that triggering NOD2 transforms inflammatory Ly6Chigh monocytes into Ly6Clow monocytes that look and function like patrolling cells. Highlights d Triggering NOD2 converts Ly6Chigh into Ly6Clow patrolling monocytes. GSE101496 d Converted Ly6Chigh monocytes express typical markers of patrolling monocytes d Triggering NOD2 increases crawling of converted Ly6Chigh monocytes d Triggering NOD2 converts human primary CD142+ CD16À into CD14± CD162+ monocytes. 2017, Cell Reports 20, 1830–1843 August 22, 2017 a 2017 The Author(s).

SUMMARY

INTRODUCTION

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES