Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium.
The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia.
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Marzena
M
Schiwon
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany; Clinic for Anesthesiology, University Clinic of Bonn, 53127 Bonn, Germany.
Christina
C
Weisheit
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Lars
L
Franken
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Sebastian
S
Gutweiler
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Akanksha
A
Dixit
Medizinische Klinik III, University Clinic Hamburg Eppendorf, 20246 Hamburg, Germany.
Catherine
C
Meyer-Schwesinger
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Judith-Mira
JM
Pohl
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Nicholas J
NJ
Maurice
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Stephanie
S
Thiebes
Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany.
Kristina
K
Lorenz
Life and Medical Sciences Institute, Friedrich-Wilhelms-Universität, 53115 Bonn, Germany.
Thomas
T
Quast
German Center for Neurodegenerative Diseases (DZNE), 53125 Bonn, Germany.
Martin
M
Fuhrmann
Clinic for Anesthesiology, University Clinic of Bonn, 53127 Bonn, Germany.
Georg
G
Baumgarten
Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany.
Martin J
MJ
Lohse
Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, 3000 KU Leuven, Belgium.
Ghislain
G
Opdenakker
Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, 52062 Aachen, Germany.
Jürgen
J
Bernhagen
Yale University School of Medicine, New Haven, CT 06510, USA.
Rick
R
Bucala
Medizinische Klinik III, University Clinic Hamburg Eppendorf, 20246 Hamburg, Germany.
Ulf
U
Panzer
Life and Medical Sciences Institute, Friedrich-Wilhelms-Universität, 53115 Bonn, Germany.
Waldemar
W
Kolanus
Cellular and Molecular Pathology, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
Hermann-Josef
HJ
Gröne
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Natalio
N
Garbi
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Wolfgang
W
Kastenmüller
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany.
Percy A
PA
Knolle
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany. Electronic address: ckurts@web.de.
Christian
C
Kurts
Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany. Electronic address: daniel.robert.engel@gmail.com.
Daniel R
DR
Engel
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001424:Bacterial Infections / Q000276:immunology*; D054426:Chemokine CXCL2 / Q000276:immunology; D005260:Female; D007154:Immune System Diseases; D007700:Kinetics; D007960:Leukocyte Disorders; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014552:Urinary Tract Infections / Q000276:immunology*
D000950:Antigens, Ly; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C494192:Ly-6C antigen, mouse; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse