The Triggering Receptor Expressed on Myeloid Cells 2 Inhibits Complement Component 1q Effector Mechanisms and Exerts Detrimental Effects during Pneumococcal Pneumonia

Phagocytosis and inflammation within the lungs is crucial for host defense during bacterial pneumonia. Triggering receptor expressed on myeloid cells (TREM)-2 was proposed to negatively regulate TLR-mediated responses and enhance phagocytosis by macrophages, but the role of TREM-2 in respiratory tract infections is unknown. Here, we established the presence of TREM-2 on alveolar macrophages (AM) and explored the function of TREM-2 in the innate immune response to pneumococcal infection in vivo. Unexpectedly, we found Trem-2(-/-) AM to display augmented bacterial phagocytosis in vitro and in vivo compared to WT AM. Mechanistically, we detected that in the absence of TREM-2, pulmonary macrophages selectively produced elevated complement component 1q (C1q) levels. We found that these increased C1q levels depended on peroxisome proliferator-activated receptor-δ (PPAR-δ) activity and were responsible for the enhanced phagocytosis of bacteria. Upon infection with S. pneumoniae, Trem-2(-/-) mice exhibited an augmented bacterial clearance from lungs, decreased bacteremia and improved survival compared to their WT counterparts. This work is the first to disclose a role for TREM-2 in clinically relevant respiratory tract infections and demonstrates a previously unknown link between TREM-2 and opsonin production within the lungs

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 infection

Elevated phagocytosis of bacteria by TREM-2 deficient AM.

<p>(<b>A</b>) WT and <i>Trem-2</i>^−/− BMDM (n = 4–5 per genotype) were incubated with FITC labeled <i>S. pneumoniae</i> (MOI 100) and after 1 h phagocytosis was assessed using FACS. (<b>B–C</b>) WT and <i>Trem-2</i>^−/− AM (n = 4 per genotype) were incubated with FITC labeled <i>S. pneumoniae</i> (<b>B</b>) or <i>E. coli</i> (<b>C</b>) (MOI of 100) and phagocytosis was assessed using FACS 1 h later. (<b>D</b>) Elevated phagocytosis of <i>S. pneumoniae</i> by <i>Trem-2</i>^−/− AM as determined using confocal microscopy as described in the M&M section. The percentage of cells that contain bacteria is depicted (n = 4–5 per genotype). (<b>E–F</b>) WT and <i>Trem-2</i>^−/− AM (n = 4–5 per genotype) were incubated with FITC labeled <i>S. pneumoniae</i> (MOI 100) under either serum free conditions (SFM) or the bacteria were pre-opsonised with 10% anti-pneumococcal serotype III capsular antibody (ST3-Ab) (<b>E</b>) or 10% pooled WT mouse serum (<b>F</b>) for 30 min before addition to the cells. Phagocytosis was assessed 1 h later. (<b>G</b>) WT and <i>Trem-2</i>^−/− AM (n = 4 per genotype) were incubated with 1 µg/ml FITC labeled BSA or FITC labeled <i>S. pneumoniae</i> (MOI 100) and phagocytosis was assessed 1 h later by FACS. (<b>H</b>) WT and <i>Trem-2</i>^−/− AM (n = 4 per genotype) were incubated with FITC labeled <i>S. pneumoniae</i> strain 19A (MOI 100) and phagocytosis was assessed 1 h later by FACS. (<b>I–L</b>) WT and <i>Trem-2</i>^−/− mice (n = 7 mice per genotype) were intranasally infected with 10⁶ CFU FITC labeled <i>S. pneumoniae</i> for 4 h and in vivo phagocytosis by AM (<b>I–J</b>) and neutrophils (<b>K–L</b>) was determined. <b>J</b> and <b>L</b> show representative FACS plots of data in <b>I</b> and <b>K</b>. (<b>M</b>) WT and <i>Trem-2</i>^−/− mice (n = 6 mice per genotype) were intranasally infected with 10⁵ CFU <i>S. pneumoniae</i> and bacterial CFUs were enumerated 24 h post infection in the lung and BALF. All data represent mean ± SEM versus WT unless otherwise indicated. Data in (<b>A–C, F and H</b>) are representative of three independent experiments and all other data are representative of two independent experiments. * p<0.05, ** p<0.005, **** p<0.0001.</p