title: The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung.
abstract: Much of the biology surrounding macrophage functional specificity has arisen through examining inflammation-induced polarizing signals, but this also occurs in homeostasis, requiring tissue-specific environmental triggers that influence macrophage phenotype and function. The TAM receptor family of receptor tyrosine kinases (Tyro3, Axl and MerTK) mediates the non-inflammatory removal of apoptotic cells by phagocytes through the bridging phosphatidylserine-binding molecules growth arrest-specific 6 (Gas6) or Protein S. We show that one such TAM receptor (Axl) is exclusively expressed on mouse airway macrophages, but not interstitial macrophages and other lung leukocytes, under homeostatic conditions and is constitutively ligated to Gas6. Axl expression is potently induced by granulocyte-macrophage colony-stimulating factor expressed in the healthy and inflamed airway, and by type I interferon or Toll-like receptor-3 stimulation on human and mouse macrophages, indicating potential involvement of Axl in apoptotic cell removal under inflammatory conditions. Indeed, an absence of Axl does not cause sterile inflammation in health, but leads to exaggerated lung inflammatory disease upon influenza infection. These data imply that Axl allows specific identification of airway macrophages, and that its expression is critical for macrophage functional compartmentalization in the airspaces or lung interstitium. We propose that this may be a critical feature to prevent excessive inflammation because of secondary necrosis of apoptotic cells that have not been cleared by efferocytosis.
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Fujimori
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Aleksander M
authors.initials: AM
authors.lastname: Grabiec
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.|University of Manchester NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, U.K.
authors.forename: Manminder
authors.initials: M
authors.lastname: Kaur
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bell
authors.affiliation: AstraZeneca R&D Mölndal, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujino
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Cook
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Freya R
authors.initials: FR
authors.lastname: Svedberg
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
authors.affiliation: AstraZeneca R&D Mölndal, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Rose A
authors.initials: RA
authors.lastname: Maciewicz
authors.affiliation: University of Manchester NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, U.K.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, Manchester University, Core Technology Facility, 46 Grafton Street, Manchester. M13 9NT, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Hussell
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017293:Protein S / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6