title: Resolution of acute inflammation bridges the gap between innate and adaptive immunity.
abstract: Acute inflammation is traditionally characterized by polymorphonuclear leukocytes (PMN) influx followed by phagocytosing macrophage (Mφs) that clear injurious stimuli leading to resolution and tissue homeostasis. However, using the peritoneal cavity, we found that although innate immune-mediated responses to low-dose zymosan or bacteria resolve within days, these stimuli, but not hyperinflammatory stimuli, trigger a previously overlooked second wave of leukocyte influx into tissues that persists for weeks. These cells comprise distinct populations of tissue-resident Mφs (resMφs), Ly6c(hi) monocyte-derived Mφs (moMφs), monocyte-derived dendritic cells (moDCs), and myeloid-derived suppressor cells (MDSCs). Postresolution mononuclear phagocytes were observed alongside lymph node expansion and increased numbers of blood and peritoneal memory T and B lymphocytes. The resMφs and moMφs triggered FoxP3 expression within CD4 cells, whereas moDCs drive T-cell proliferation. The resMφs preferentially clear apoptotic PMNs and migrate to lymph nodes to bring about their contraction in an inducible nitric oxide synthase-dependent manner. Finally, moMφs remain in tissues for months postresolution, alongside altered numbers of T cells collectively dictating the magnitude of subsequent acute inflammatory reactions. These data challenge the prevailing idea that resolution leads back to homeostasis and asserts that resolution acts as a bridge between innate and adaptive immunity, as well as tissue reprogramming.
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Justine
authors.initials: J
authors.lastname: Newson
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Melanie
authors.initials: M
authors.lastname: Stables
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Efthimia
authors.initials: E
authors.lastname: Karra
authors.affiliation: Research Department of Haematology, Cancer Immunology Unit, University College London Cancer Institute, London, United Kingdom; and.
authors.forename: Frederick
authors.initials: F
authors.lastname: Arce-Vargas
authors.affiliation: Research Department of Haematology, Cancer Immunology Unit, University College London Cancer Institute, London, United Kingdom; and.
authors.forename: Sergio
authors.initials: S
authors.lastname: Quezada
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Madhur
authors.initials: M
authors.lastname: Motwani
authors.affiliation: Universitätsklinikum Regensburg, Innere Medizin II/Nephrologie-Transplantation, Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Simon
authors.initials: S
authors.lastname: Yona
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Audzevich
authors.affiliation: Division of Medicine, Centre for Clinical Pharmacology and Therapeutics, University College London, London, United Kingdom;
authors.forename: Derek W
authors.identifier: http://orcid.org/0000-0003-3476-0844
authors.initials: DW
authors.lastname: Gilroy
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D015054:Zymosan / Q000633:toxicity
chemical_list: D051858:Forkhead Transcription Factors; C472854:Foxp4 protein, mouse; D015054:Zymosan