title: Circulating Soluble IL-6R but Not ADAM17 Activation Drives Mononuclear Cell Migration in Tissue Inflammation.
abstract: Neutrophil and mononuclear cell infiltration during inflammatory processes is highly regulated. The first cells at the site of infection or inflammation are neutrophils, followed by mononuclear cells. IL-6 plays an important role during inflammatory states. It has been shown in several models that the soluble form of IL-6R (sIL-6R) is involved in the recruitment of mononuclear cells by a mechanism called IL-6 trans-signaling. It had been speculated that sIL-6R was generated at the site of inflammation by shedding from neutrophils via activation of the metalloprotease ADAM17. Attempts to genetically delete the floxed ADAM17 gene selectively in myeloid cells infiltrating an air pouch cavity upon injection of carrageenan failed because in transgenic mice, LysMcredid not lead to appreciable loss of the ADAM17 protein in these cells. We therefore used ADAM17 hypomorphic mice, which only express ∼5% of ADAM17 wild-type levels in all tissues and show virtually no shedding of all tested ADAM17 substrates, to clarify the role of ADAM17 during local inflammation in the murine air pouch model. In the present study, we demonstrate that although IL-6 and the trans-signaling mechanism is mandatory for cellular infiltration in this model, it is not ADAM17-mediated shedding of IL-6R within the pouch that orchestrates this inflammatory process. Instead, we demonstrate that sIL-6R is infiltrating from the circulation in an ADAM17-independent process. Our data suggest that this infiltrating sIL-6R, which is needed for IL-6 trans-signaling, is involved in the controlled resolution of an acute inflammatory episode.
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Neele
authors.initials: N
authors.lastname: Schumacher
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Schwarz
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Dana
authors.initials: D
authors.lastname: Dohr
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lokau
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Christoph
authors.identifier: 0000-0003-4939-6950
authors.initials: C
authors.lastname: Garbers
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and rosejohn@biochem.uni-kiel.de.
authors.forename: Stefan
authors.identifier: 0000-0002-7519-3279
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany; and.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002351:Carrageenan; D002465:Cell Movement; D002478:Cells, Cultured; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D002351:Carrageenan; D000072198:ADAM17 Protein