[en] Resident tissue macrophages (RTM) can fulfill various tasks during development, homeostasis, inflammation and repair. In the lung, non-alveolar RTM, called interstitial macrophages (IM), importantly contribute to tissue homeostasis but remain little characterized. Here we show, using single-cell RNA-sequencing (scRNA-seq), two phenotypically distinct subpopulations of long-lived monocyte-derived IM, i.e. CD206(+) and CD206(-)IM, as well as a discrete population of extravasating CD64(+)CD16.2(+) monocytes. CD206(+) IM are peribronchial self-maintaining RTM that constitutively produce high levels of chemokines and immunosuppressive cytokines. Conversely, CD206(-)IM preferentially populate the alveolar interstitium and exhibit features of antigen-presenting cells. In addition, our data support that CD64(+)CD16.2(+) monocytes arise from intravascular Ly-6C(lo) patrolling monocytes that enter the tissue at steady-state to become putative precursors of CD206(-)IM. This study expands our knowledge about the complexity of lung IM and reveals an ontogenic pathway for one IM subset, an important step for elaborating future macrophage-targeted therapies.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Schyns, Joey ; Université de Liège - ULiège > I3-Immunophysiology
Bai, Qiang ; Université de Liège - ULiège > I3-Immunophysiology
Farnir, Frédéric ; Université de Liège - ULiège > Dpt. de gestion vétérinaire des Ressources Animales (DRA) > Biostatistiques et bioinformatique appliquées aux sc. vétér.
Pirottin, Dimitri ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Département des sciences fonctionnelles (DSF)
Ginhoux, Florent
Boeckxstaens, Guy
Bureau, Fabrice ; Université de Liège - ULiège > Vice-Recteur à la Recherche
Marichal, Thomas ; Université de Liège - ULiège > I3-Immunophysiology
Language :
English
Title :
Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung.
Publication date :
2019
Journal title :
Nature Communications
eISSN :
2041-1723
Publisher :
Nature Publishing Group, United Kingdom
Volume :
10
Issue :
1
Pages :
3964
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
H2020 - 801823 - IM-ID - Defining the intrinsic transcriptional programs and the microenvironmental signals tailoring lung Interstitial Macrophage IDentity
Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Okabe, Y. & Medzhitov, R. Tissue biology perspective on macrophages. Nat. Immunol. 17, 9–17 (2016).
Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).
van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).
Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).
Takata, K. et al. Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function. Immunity 47, 183–198 e6 (2017).
Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med 210, 1977–1992 (2013).
Hussell, T. & Bell, T. J. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14, 81–93 (2014).
Schneider, C. et al. Induction of the nuclear receptor PPAR-gamma by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).
Bedoret, D. et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J. Clin. Invest 119, 3723–3738 (2009).
Liegeois, M., Legrand, C., Desmet, C. J., Marichal, T. & Bureau, F. The interstitial macrophage: a long-neglected piece in the puzzle of lung immunity. Cell Immunol. 330, 91–96 (2018).
Schyns, J., Bureau, F. & Marichal, T. Lung interstitial macrophages: past, present, and future. J. Immunol. Res 2018, 5160794 (2018).
Kawano, H. et al. IL-10-producing lung interstitial macrophages prevent neutrophilic asthma. Int Immunol. 28, 489–501 (2016).
von Mutius, E. The microbial environment and its influence on asthma prevention in early life. J. Allergy Clin. Immunol. 137, 680–689 (2016).
Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).
Sabatel, C. et al. Exposure to bacterial CpG DNA protects from airway allergic inflammation by expanding regulatory lung interstitial macrophages. Immunity 46, 457–473 (2017).
Hoppstadter, J. et al. Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages. Respir. Res 11, 124 (2010).
Draijer, C. et al. Human asthma is characterized by more IRF5+ M1 and CD206+ M2 macrophages and less IL-10+ M2-like macrophages around airways compared with healthy airways. J. Allergy Clin. Immunol. 140, 280–283.e3 (2017).
Gibbings, S. L. et al. Three unique interstitial macrophages in the murine lung at steady state. Am. J. Respir. Cell Mol. Biol. 57, 66–76 (2017).
Chakarov, S. et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363, pii: eaau0964 (2019).
Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).
Mesnil, C. et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Invest 126, 3279–3295 (2016).
Cohen, M. et al. Lung single-cell signaling interaction map reveals basophil role in macrophage imprinting. Cell 175, 1031–1044 e18 (2018).
Scott, C. L. et al. The transcription factor ZEB2 is required to maintain the tissue-specific identities of macrophages. Immunity 49, 312–325 e5 (2018).
Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39, 599–610 (2013).
Tan, S. Y. S. & Krasnow, M. A. Developmental origin of lung macrophage diversity. Development 143, 1318–1327 (2016).
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).
Hanna, R. N. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat. Immunol. 12, 778–785 (2011).
Garlanda, C., Bottazzi, B., Bastone, A. & Mantovani, A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev. Immunol. 23, 337–366 (2005).
Bouabe, H., Liu, Y., Moser, M., Bosl, M. R. & Heesemann, J. Novel highly sensitive IL-10-beta-lactamase reporter mouse reveals cells of the innate immune system as a substantial source of IL-10 in vivo. J. Immunol. 187, 3165–3176 (2011).
La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).
Street, K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genom. 19, 477 (2018).
Mildner, A. et al. Genomic characterization of murine monocytes reveals C/EBPbeta transcription factor dependence of Ly6C(−) Cells. Immunity 46, 849–862 e7 (2017).
Rodero, M. P. et al. Immune surveillance of the lung by migrating tissue monocytes. eLife 4, e07847 (2015).
Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).
Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).
Macosko, E. Z. et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161, 1202–1214 (2015).
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415 e13 (2018).