title: Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair.
abstract: Macrophage gene expression determines phagocyte responses and effector functions. Macrophage plasticity has been mainly addressed in in vitro models that do not account for the environmental complexity observed in vivo. In this study, we show that microarray gene expression profiling revealed a highly dynamic landscape of transcriptomic changes of Ly6C(pos)CX3CR1(lo) and Ly6C(neg)CX3CR1(hi) macrophage populations during skeletal muscle regeneration after a sterile damage. Systematic gene expression analysis revealed that the time elapsed, much more than Ly6C status, was correlated with the largest differential gene expression, indicating that the time course of inflammation was the predominant driving force of macrophage gene expression. Moreover, Ly6C(pos)/Ly6C(neg) subsets could not have been aligned to canonical M1/M2 profiles. Instead, a combination of analyses suggested the existence of four main features of muscle-derived macrophages specifying important steps of regeneration: 1) infiltrating Ly6C(pos) macrophages expressed acute-phase proteins and exhibited an inflammatory profile independent of IFN-γ, making them damage-associated macrophages; 2) metabolic changes of macrophages, characterized by a decreased glycolysis and an increased tricarboxylic acid cycle/oxidative pathway, preceded the switch to and sustained their anti-inflammatory profile; 3) Ly6C(neg) macrophages, originating from skewed Ly6C(pos) cells, actively proliferated; and 4) later on, restorative Ly6C(neg) macrophages were characterized by a novel profile, indicative of secretion of molecules involved in intercellular communications, notably matrix-related molecules. These results show the highly dynamic nature of the macrophage response at the molecular level after an acute tissue injury and subsequent repair, and associate a specific signature of macrophages to predictive specialized functions of macrophages at each step of tissue injury/repair.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
authors.forename: Tamas
authors.initials: T
authors.lastname: Varga
authors.affiliation: Institut NeuroMyoGène, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France; CNRS UMR 5510, 69100 Villeurbanne, France; INSERM U1217, 69100 Villeurbanne, France;
authors.forename: Rémi
authors.initials: R
authors.lastname: Mounier
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
authors.forename: Attila
authors.initials: A
authors.lastname: Horvath
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France;
authors.forename: Sylvain
authors.identifier: 0000-0002-4612-1655
authors.initials: S
authors.lastname: Cuvellier
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France;
authors.forename: Florent
authors.identifier: 0000-0002-4439-5070
authors.initials: F
authors.lastname: Dumont
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; Bioinformatics Core Facility, University of Debrecen, 4032 Debrecen, Hungary;
authors.forename: Szilard
authors.identifier: 0000-0002-9722-251X
authors.initials: S
authors.lastname: Poliska
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France;
authors.forename: Hamida
authors.initials: H
authors.lastname: Ardjoune
authors.affiliation: Institut NeuroMyoGène, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France; CNRS UMR 5510, 69100 Villeurbanne, France; INSERM U1217, 69100 Villeurbanne, France;
authors.forename: Gaëtan
authors.identifier: 0000-0002-5845-9223
authors.initials: G
authors.lastname: Juban
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827; and Hungarian Academy of Sciences - Debrecen "Lendulet" Immunogenomics Research Group, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Laszlo
authors.identifier: 0000-0001-6653-2155
authors.initials: L
authors.lastname: Nagy
authors.affiliation: Institut NeuroMyoGène, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France; CNRS UMR 5510, 69100 Villeurbanne, France; INSERM U1217, 69100 Villeurbanne, France; INSERM U1016, Institut Cochin, 75014 Paris, France; benedicte.chazaud@inserm.fr.
authors.forename: Bénédicte
authors.identifier: 0000-0002-1262-502X
authors.initials: B
authors.lastname: Chazaud
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics* / Q000276:immunology; D014945:Wound Healing / Q000235:genetics* / Q000276:immunology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine