TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance

Weber, Benjamin; Schuster, Steffen; Zysset, Daniel; Rihs, Silvia; Dickgreber, Nina; Schürch, Christian; Riether, Carsten; Siegrist, Mark; Schneider, Christoph; Pawelski, Helga; Gurzeler, Ursina; Ziltener, Pascal; Genitsch, Vera; Tacchini-Cottier, Fabienne; Ochsenbein, Adrian; Hofstetter, Willy; Kopf, Manfred; Kaufmann, Thomas; Oxenius, Annette; Reith, Walter; Saurer, Leslie; Mueller, Christoph

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Title		TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance
Authors		Weber, Benjamin Schuster, Steffen Zysset, Daniel Rihs, Silvia Dickgreber, Nina Schürch, Christian Riether, Carsten Siegrist, Mark Schneider, Christoph Pawelski, Helga Gurzeler, Ursina Ziltener, Pascal Genitsch, Vera Tacchini-Cottier, Fabienne Ochsenbein, Adrian Hofstetter, Willy Kopf, Manfred Kaufmann, Thomas Oxenius, Annette Reith, Walter Saurer, Leslie Mueller, Christoph show all authors [1 - 22]
Published in		PLOS Pathogens. 2014, vol. 10, no. 1, p. e1003900
Abstract		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.
Identifiers		DOI: 10.1371/journal.ppat.1003900 PMID: 24453980
Full text		Article (Published version) (3.3 MB) - Free access
Structures		Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research group		Groupe Reith Walter (pathologie et immunologie) (282)
Citation (ISO format)		WEBER, Benjamin et al. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. In: PLOS Pathogens, 2014, vol. 10, n° 1, p. e1003900. https://archive-ouverte.unige.ch/unige:36447