title: CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels.
abstract: The CC chemokine ligand-2 (CCL2) and its receptor CCR2 are essential for monocyte trafficking under inflammatory conditions. However, the mechanisms that determine the intensity and duration of alveolar monocyte accumulation in response to CCL2 gradients in inflamed lungs have not been resolved. To determine the potential role of CCR2-expressing monocytes in regulating alveolar CCL2 levels, we compared leukocyte recruitment kinetics and alveolar CCL2 levels in wild-type and CCR2-deficient mice in response to intratracheal LPS challenge. In wild-type mice, LPS elicited a dose- and time-dependent alveolar monocyte accumulation accompanied by low CCL2 levels in bronchoalveolar lavage fluid (BALF). In contrast, LPS-treated CCR2-deficient mice lacked alveolar monocyte accumulation, which was accompanied by relatively high CCL2 levels in BALF. Similarly, wild-type mice that were treated systemically with the blocking anti-CCR2 antibody MC21 completely lacked LPS-induced alveolar monocyte trafficking that was associated with high CCL2 levels in BALF. Intratracheal application of anti-CCR2 antibody MC21 to locally block CCR2 on both resident and recruited cells did not affect LPS-induced alveolar monocyte trafficking but led to significantly increased BALF CCL2 levels. Reciprocally bone marrow-transplanted, LPS-treated wild-type and CCR2-deficient mice showed a strict inverse relationship between alveolar monocyte recruitment and BALF CCL2 levels. In addition, freshly isolated human and mouse monocytes were capable of integrating CCL2 in vitro. LPS-induced alveolar monocyte accumulation is accompanied by monocytic CCR2-dependent consumption of CCL2 levels in the lung. This feedback loop may limit the intensity of monocyte recruitment to inflamed lungs and play a role in the maintenance of homeostasis.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Justus-Liebig-University, Klinikstr. 36, Giessen 35392, Germany. Ulrich.A.Maus@med.uni-giessen.de
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
authors.forename: Sandra
authors.initials: S
authors.lastname: Wellmann
authors.forename: Christine
authors.initials: C
authors.lastname: Hampl
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Mrigank
authors.initials: M
authors.lastname: Srivastava
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: M Brett
authors.initials: MB
authors.lastname: Everhart
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Rainer M
authors.initials: RM
authors.lastname: Bohle
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lohmeyer
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D002678:Chimera; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000503:physiopathology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D014132:Trachea
chemical_list: D000906:Antibodies; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D019707:Receptors, Chemokine