tetano
Editor, Senior Moderator
PLoS Pathog. 2014 Jan;10(1):e1003900. doi: 10.1371/journal.ppat.1003900. Epub 2014 Jan 16.
TREM-1 Deficiency Can Attenuate Disease Severity without Affecting Pathogen Clearance.
Weber B1, Schuster S2, Zysset D1, Rihs S1, Dickgreber N1, Sch?rch C3, Riether C4, Siegrist M4, Schneider C5, Pawelski H5, Gurzeler U6, Ziltener P7, Genitsch V1, Tacchini-Cottier F2, Ochsenbein A8, Hofstetter W4, Kopf M5, Kaufmann T6, Oxenius A7, Reith W9, Saurer L1, Mueller C1.
Author information
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.
PMID:
24453980
[PubMed - in process]
Free full text
http://www.ncbi.nlm.nih.gov/pubmed/24453980
TREM-1 Deficiency Can Attenuate Disease Severity without Affecting Pathogen Clearance.
Weber B1, Schuster S2, Zysset D1, Rihs S1, Dickgreber N1, Sch?rch C3, Riether C4, Siegrist M4, Schneider C5, Pawelski H5, Gurzeler U6, Ziltener P7, Genitsch V1, Tacchini-Cottier F2, Ochsenbein A8, Hofstetter W4, Kopf M5, Kaufmann T6, Oxenius A7, Reith W9, Saurer L1, Mueller C1.
Author information
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.
PMID:
24453980
[PubMed - in process]
Free full text
http://www.ncbi.nlm.nih.gov/pubmed/24453980