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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., Author Summary Bacterial respiratory tract infections are a major cause of morbidity and mortality, and Streptococcus pneumoniae (S. pneumoniae) remains the main cause of community acquired pneumonia worldwide. The continued rise in antibiotic resistance stresses the need for better insights into the host defense mechanisms associated with pneumococcal pneumonia. The early innate immune response that constitutes bacterial phagocytosis, complement activation and inflammation is critical for the outcome during pneumonia. The triggering receptor expressed on myeloid cells 2 (TREM-2) has recently been shown to be both a negative regulator of the inflammatory response and a promoter of phagocytosis, but its contribution to pneumonia remains unknown. In our study, we unexpectedly found that alveolar macrophage expressed TREM-2 is detrimental in bacterial phagocytosis and clearance during pneumococcal pneumonia. This occurred via the suppressive effects of TREM-2 on complement component 1q (C1q), an important regulator of bacterial phagocytosis that is crucial for the host response during pneumonia. Thus, targeting the TREM-2 pathway could be used as a novel strategy for modulating C1q production and pulmonary innate immune responses, which could be of clinical relevance during pneumonia and other respiratory tract infections.

The generation of terminal deoxynucleotidyl transferase knockout mice (TdT0) has demonstrated that TdT is the only major activity involved in N region addition. This enzyme generates diversity by adding random nucleotides at the V-D-J junctions and by disrupting the formation of repetitive "homology-directed" junctions. Several studies have demonstrated that the Ig heavy chain third complementarity-determining region (H-CDR3) and the N region play a critical role: 1) in distinguishing between polyreactive and monospecific combining sites in natural and Ag-induced Abs; and 2) in the specificity and polyreactivity of natural autoantibodies (autoAbs) and in particular of anti-DNA Abs. To examine the impact of the lack of TdT on the natural autoAb repertoire in adult mice, we have stimulated TdT0 and TdT+ littermates with LPS. Serum studies demonstrate that TdT is not critical for the generation of B cells expressing autoAbs including anti-DNA Abs and rheumatoid factors. However, the generation of a large collection of hybridomas indicates that the frequencies of these cells are reduced in TdT0 mice mainly due to a lower incidence of polyreactivity; also, the lack of N region diversity seems to negatively affect the affinity of anti-DNA Abs. The physiologic relevance of these data is discussed.