TREM-1 activation alters the dynamics of pulmonary IRAK-M expression in vivo and improves host defense during pneumococcal pneumonia.
Triggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of TLR-mediated inflammation during bacterial infections. Thus far, TREM-1 is primarily associated with unwanted signs of overwhelming inflammation, rendering it an attractive target for conditions such as sepsis. Respiratory tract infections are the leading cause of sepsis, but the biological role of TREM-1 therein is poorly understood. To determine the function of TREM-1 in pneumococcal pneumonia, we first established TREM-1 up-regulation in infected lungs and human plasma together with augmented alveolar macrophage responsiveness toward Streptococcus pneumoniae. Mice treated with an agonistic TREM-1 Ab and infected with S. pneumoniae exhibited an enhanced early induction of the inflammatory response that was indirectly associated with lower levels of negative regulators of TLR signaling in lung tissue in vivo. Later in infection, TREM-1 engagement altered S. pneumoniae-induced IRAK-M (IL-1R-associated kinase-M) kinetics so as to promote the resolution of pneumonia and remarkably led to an accelerated elimination of bacteria and consequently improved survival. These data show that TREM-1 exerts a protective role in the innate immune response to a common bacterial infection and suggest that caution should be exerted in modulating TREM-1 activity during certain clinically relevant bacterial infections.
Lagler
Heimo
H
Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, Vienna, Austria.
Sharif
Omar
O
Haslinger
Isabella
I
Matt
Ulrich
U
Stich
Karin
K
Furtner
Tanja
T
Doninger
Bianca
B
Schmid
Katharina
K
Gattringer
Rainer
R
de Vos
Alex F
AF
Knapp
Sylvia
S
D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D011018:Pneumonia, Pneumococcal / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D013296:Streptococcus pneumoniae; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse