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

Abstract

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.

TREM2, Microglia, and Neurodegenerative Diseases

“…As previously discussed, the TREM2 gene is highly expressed in a subset of myeloid cell typesnamely, microglia in the CNS, osteoclasts in the bone, and other tissue-specific macrophages, including Kupffer cells, as well as alveolar, intestinal, and peritoneal macrophages [58,73,[90][91][92][93][94][95]. Bone marrow cells and blood monocytes express low to undetectable levels of TREM2, although expression can be induced upon differentiation of the former into macrophages or dendritic cells in vitro [50,87,91].…”

Triggering receptor expressed on myeloid cells receptor family modulators: a patent review

“…In contrast, alveolar macrophages isolated from TREM-2 −/− mice actually exhibited enhanced phagocytosis of E. coli and S. pneumonia associated with an increased level of complement component 1q (11). This may explain why TREM-2-deficient mice had a better survival rate than control wild-type mice following infection with S. pneumoniae (11). …”

“…TREM-2 −/− mice experienced improved survival and enhanced bacterial clearance following infection with Streptococcus pneumoniae when compared to control wild-type mice (11). Moreover, macrophages isolated from TREM-2-deficient mice displayed greater induction of cytokines (i.e.…”

TREM2-Ligand Interactions in Health and Disease

“…For example, some studies have shown ectopic expression of TREM2 is sufficient to promote phagocytosis in non-myeloid cells [25, 122]. However a most interesting study from Knapp and colleagues demonstrated Trem2 deficiency had opposite effects on phagocytosis by bone marrow and alveolar macrophages [144]. In the context of neurodegenerative disease, it has often been assumed that TREM2 has a major role in phagocytosis of debris.…”

“…TREM2 was reported to inhibit expression of C1q in alveolar macrophages [150] and C1q is expressed by microglia during development and improperly during AD to prune neuronal synapses [151]. …”