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 th...
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2014
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oai:doaj.org-article:42262ea844a64ff3b8f92dc971b3e0fb2021-11-18T06:07:05ZTREM-1 deficiency can attenuate disease severity without affecting pathogen clearance.1553-73661553-737410.1371/journal.ppat.1003900https://doaj.org/article/42262ea844a64ff3b8f92dc971b3e0fb2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24453980/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Triggering 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.Benjamin WeberSteffen SchusterDaniel ZyssetSilvia RihsNina DickgreberChristian SchürchCarsten RietherMark SiegristChristoph SchneiderHelga PawelskiUrsina GurzelerPascal ZiltenerVera GenitschFabienne Tacchini-CottierAdrian OchsenbeinWilly HofstetterManfred KopfThomas KaufmannAnnette OxeniusWalter ReithLeslie SaurerChristoph MuellerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 1, p e1003900 (2014) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Benjamin Weber Steffen Schuster Daniel Zysset Silvia Rihs Nina Dickgreber Christian Schürch Carsten Riether Mark Siegrist Christoph Schneider Helga Pawelski Ursina Gurzeler Pascal Ziltener Vera Genitsch Fabienne Tacchini-Cottier Adrian Ochsenbein Willy Hofstetter Manfred Kopf Thomas Kaufmann Annette Oxenius Walter Reith Leslie Saurer Christoph Mueller TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| description |
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. |
| format |
article |
| author |
Benjamin Weber Steffen Schuster Daniel Zysset Silvia Rihs Nina Dickgreber Christian Schürch Carsten Riether Mark Siegrist Christoph Schneider Helga Pawelski Ursina Gurzeler Pascal Ziltener Vera Genitsch Fabienne Tacchini-Cottier Adrian Ochsenbein Willy Hofstetter Manfred Kopf Thomas Kaufmann Annette Oxenius Walter Reith Leslie Saurer Christoph Mueller |
| author_facet |
Benjamin Weber Steffen Schuster Daniel Zysset Silvia Rihs Nina Dickgreber Christian Schürch Carsten Riether Mark Siegrist Christoph Schneider Helga Pawelski Ursina Gurzeler Pascal Ziltener Vera Genitsch Fabienne Tacchini-Cottier Adrian Ochsenbein Willy Hofstetter Manfred Kopf Thomas Kaufmann Annette Oxenius Walter Reith Leslie Saurer Christoph Mueller |
| author_sort |
Benjamin Weber |
| title |
TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| title_short |
TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| title_full |
TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| title_fullStr |
TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| title_full_unstemmed |
TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| title_sort |
trem-1 deficiency can attenuate disease severity without affecting pathogen clearance. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/42262ea844a64ff3b8f92dc971b3e0fb |
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