TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance.
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1(-/-) mice are viable, fertile and show no altered hematopoietic compartment. In CD4(+) T cell- and dextran sodium sulfate-induced models of colitis, Trem1(-/-) mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1(-/-) mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1(-/-) mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1(-/-) mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1(+/+) controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control.
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Benjamin
B
Weber
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Steffen
S
Schuster
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Daniel
D
Zysset
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Silvia
S
Rihs
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Nina
N
Dickgreber
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland ; Department of Clinical Research, University of Bern, Bern, Switzerland.
Christian
C
Schürch
Department of Clinical Research, University of Bern, Bern, Switzerland.
Carsten
C
Riether
Department of Clinical Research, University of Bern, Bern, Switzerland.
Mark
M
Siegrist
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Christoph
C
Schneider
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Helga
H
Pawelski
Institute of Pharmacology, University of Bern, Bern, Switzerland.
Ursina
U
Gurzeler
Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
Pascal
P
Ziltener
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Vera
V
Genitsch
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Fabienne
F
Tacchini-Cottier
Department of Clinical Research, University of Bern, Bern, Switzerland ; Department of Medical Oncology, University of Bern, Bern, Switzerland.
Adrian
A
Ochsenbein
Department of Clinical Research, University of Bern, Bern, Switzerland.
Willy
W
Hofstetter
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Manfred
M
Kopf
Institute of Pharmacology, University of Bern, Bern, Switzerland.
Thomas
T
Kaufmann
Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
Annette
A
Oxenius
Department of Pathology and Immunology, Centre Medical Universitaire, Geneva, Switzerland.
Walter
W
Reith
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Leslie
L
Saurer
Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Christoph
C
Mueller
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D009980:Influenza A virus / Q000276:immunology*; D016952:Legionella pneumophila / Q000276:immunology*; D007877:Legionnaires' Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1