Monocytes play a major role in the defense against pathogens. They are rapidly mobilized to inflamed sites where they exert both proinflammatory and regulatory effector functions. It is still poorly understood how this dynamic and exceptionally plastic system is controlled at the molecular level. Herein, we evaluated the differentiation process that occurs in Ly6Chi monocytes during oral infection by Toxoplasma gondii. Flow cytometry and single-cell analysis revealed distinct activation status and gene expression profiles in the bone marrow, the spleen and the lamina propria of infected mice. We provide further evidence that acquisition of effector functions, such as the capacity to produce interleukin-27, is accompanied by distinct waves of epigenetic programming, highlighting a role for STAT1/IRF1 in the bone marrow and AP-1/NF-κB in the periphery. This work broadens our understanding of the molecular events that occur in vivo during monocyte differentiation in response to inflammatory cues.

Institute of Biotechnology Czech Academy of Science 252 50 Vestec u prahy Czech Republic

Université Catholique de Louvain Institut de Duve Brussels Belgium

Université Libre de Bruxelles Institute for Medical Immunology and ULB Center for Research in Immunology Gosselies Belgium

Université Libre de Bruxelles Laboratoire d'Immunobiologie Gosselies Belgium

Université Libre de Bruxelles Laboratory of Cancer Epigenetics Brussels Belgium

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Guilliams M, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 2014;14:571–578. doi: 10.1038/nri3712. PubMed DOI PMC

Guilliams M, Mildner A, Yona S. Developmental and functional heterogeneity of monocytes. Immunity. 2018;49:595–613. doi: 10.1016/j.immuni.2018.10.005. PubMed DOI

Glass CK, Natoli G. Molecular control of activation and priming in macrophages. Nat. Immunol. 2016;17:26–33. doi: 10.1038/ni.3306. PubMed DOI PMC

Amit I, Winter DR, Jung S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 2016;17:18–25. doi: 10.1038/ni.3325. PubMed DOI

Ostuni R, et al. Latent enhancers activated by stimulation in differentiated cells. Cell. 2013;152:157–171. doi: 10.1016/j.cell.2012.12.018. PubMed DOI

Shalek AK, et al. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature. 2013;498:236–240. doi: 10.1038/nature12172. PubMed DOI PMC

Hand TW, et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science. 2012;337:1553–1556. doi: 10.1126/science.1220961. PubMed DOI PMC

Oldenhove G, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009;31:772–786. doi: 10.1016/j.immuni.2009.10.001. PubMed DOI PMC

Dunay IR, et al. Gr1+inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity. 2008;29:306–317. doi: 10.1016/j.immuni.2008.05.019. PubMed DOI PMC

Grainger JR, et al. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat. Med. 2013;19:713–721. doi: 10.1038/nm.3189. PubMed DOI PMC

Tamoutounour S, et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity. 2013;39:925–938. doi: 10.1016/j.immuni.2013.10.004. PubMed DOI

Bain CC, et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2013;6:498–510. doi: 10.1038/mi.2012.89. PubMed DOI PMC

Langlet C, et al. CD64 expression distinguishes monocyte-derived and conventional dendritic cells and reveals their distinct role during intramuscular immunization. J. Immunol. 2012;188:1751–1760. doi: 10.4049/jimmunol.1102744. PubMed DOI

Askenase MH, et al. Bone-marrow-resident NK cells prime monocytes for regulatory function during Infection. Immunity. 2015;42:1130–1142. doi: 10.1016/j.immuni.2015.05.011. PubMed DOI PMC

Tay S, et al. Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing. Nature. 2010;466:267–271. doi: 10.1038/nature09145. PubMed DOI PMC

Fanucchi S, Shibayama Y, Burd S, Weinberg MS, Mhlanga MM. XChromosomal contact permits transcription between coregulated genes. Cell. 2013;155:606–620. doi: 10.1016/j.cell.2013.09.051. PubMed DOI

Mashayekhi M, et al. CD8α(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites. Immunity. 2011;35:249–259. doi: 10.1016/j.immuni.2011.08.008. PubMed DOI PMC

Hall AOH, et al. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced. Pathology. 2013;37:511–523. PubMed PMC

Goriely S, Neurath MF, Goldman M. How microorganisms tip the balance between interleukin-12 family members. Nat. Rev. Immunol. 2008;8:81–86. doi: 10.1038/nri2225. PubMed DOI

Lee H-M, et al. IFNγ signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells. PLOS Pathog. 2015;11:e1004635. doi: 10.1371/journal.ppat.1004635. PubMed DOI PMC

Garber M, et al. A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. Mol. Cell. 2012;47:810–822. doi: 10.1016/j.molcel.2012.07.030. PubMed DOI PMC

McLean CY, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 2010;28:495–501. doi: 10.1038/nbt.1630. PubMed DOI PMC

Langlais D, Barreiro LB, Gros P. The macrophage IRF8 / IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J. Exp. Med. 2016;213:585–603. doi: 10.1084/jem.20151764. PubMed DOI PMC

Molle C, Goldman M, Goriely S, Alerts E. Critical role of the IFN-stimulated gene factor 3 complex in TLR-mediated IL-27p28 gene expression revealing a two-step activation process. J. Immunol. 2010;184:1784–1792. doi: 10.4049/jimmunol.0902005. PubMed DOI

Yona S, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91. doi: 10.1016/j.immuni.2012.12.001. PubMed DOI PMC

Yáñez A, et al. Granulocyte-monocyte progenitors and monocyte-dendritic cell progenitors independently produce functionally distinct monocytes. Immunity. 2017;47:890–902.e4. doi: 10.1016/j.immuni.2017.10.021. PubMed DOI PMC

Qiao Y, et al. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling. Immunity. 2013;39:454–469. doi: 10.1016/j.immuni.2013.08.009. PubMed DOI PMC

Vierbuchen T, et al. AP-1 transcription factors and the BAF complex mediate signal-dependent enhancer selection. Mol. Cell. 2017;68:1134–1146.e6. doi: 10.1016/j.molcel.2017.11.026. PubMed DOI PMC

Park SH, et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat. Immunol. 2017;18:1104–1116. doi: 10.1038/ni.3818. PubMed DOI PMC

Serbina NV, Pamer EG. Coordinating innate immune cells to optimize microbial killing. Immunity. 2008;29:672–674. doi: 10.1016/j.immuni.2008.10.003. PubMed DOI PMC

Narni-Mancinelli Emilie, Soudja Saidi M'Homa, Crozat Karine, Dalod Marc, Gounon Pierre, Geissmann Frédéric, Lauvau Grégoire. Inflammatory Monocytes and Neutrophils Are Licensed to Kill during Memory Responses In Vivo. PLoS Pathogens. 2011;7(12):e1002457. doi: 10.1371/journal.ppat.1002457. PubMed DOI PMC

Glennie ND, Volk SW, Scott P. Skin-resident CD4+ T cells protect against Leishmania major by recruiting and activating inflammatory monocytes. PLOS Pathog. 2017;13:e1006349. doi: 10.1371/journal.ppat.1006349. PubMed DOI PMC

Nakanishi Y, Sato T, Takahashi K, Ohteki T. IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo. Mucosal Immunol. 2018;11:871–880. doi: 10.1038/mi.2017.104. PubMed DOI

Terrazas, C. et al. Ly6C hi inflammatory monocytes promote susceptibility to Leishmania donovani infection. Sci. Rep. 7, 14693 (2017). PubMed PMC

Kilgore AM, et al. IL-27p28 production by XCR1 + dendritic cells and monocytes effectively predicts adjuvant-elicited CD8 + T cell responses HHS Public Access. Immunohorizons. 2018;2:1–11. doi: 10.4049/immunohorizons.1700054. PubMed DOI PMC

Goriely S, et al. Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation. Blood. 2006;107:1078–1084. doi: 10.1182/blood-2005-06-2416. PubMed DOI

Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21.29.1–21.29.9 (2015). PubMed PMC

Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat. Methods. 2012;9:357–359. doi: 10.1038/nmeth.1923. PubMed DOI PMC

Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10:R25. doi: 10.1186/gb-2009-10-3-r25. PubMed DOI PMC

Consortium TEP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74. doi: 10.1038/nature11247. PubMed DOI PMC

Zhang Y, et al. Model-based analysis of ChIP-Seq (MACS) Genome Biol. 2008;9:R137. doi: 10.1186/gb-2008-9-9-r137. PubMed DOI PMC

Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–842. doi: 10.1093/bioinformatics/btq033. PubMed DOI PMC

Ramírez F, Dündar F, Diehl S, Grüning BA, Manke T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 2014;42:W187–W191. doi: 10.1093/nar/gku365. PubMed DOI PMC

Bailey TL, et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009;37:W202–W208. doi: 10.1093/nar/gkp335. PubMed DOI PMC

Buske FA, Bodén M, Bauer DC, Bailey TL. Assigning roles to DNA regulatory motifs using comparative genomics. Bioinformatics. 2010;26:860–866. doi: 10.1093/bioinformatics/btq049. PubMed DOI PMC

Afgan E, et al. The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update. Nucleic Acids Res. 2018;46:W537–W544. doi: 10.1093/nar/gky379. PubMed DOI PMC