TREM-2 promotes macrophage survival and lung disease after respiratory viral infection.
Bottom Line: However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infection (49 d after inoculation).At this time, IL-13 and the adapter protein DAP12 promote TREM-2 cleavage to sTREM-2 that is unexpectedly active in preventing macrophage apoptosis.The results thereby define an unprecedented mechanism for a feed-forward expansion of lung macrophages (with IL-13 production and consequent M2 differentiation) that further explains how acute infection leads to chronic inflammatory disease.
Affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.Show MeSH
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Mentions: Based on the association of TREM-2 with M2 differentiation (Turnbull et al., 2006), we investigated the role of TREM-2 in macrophage-dependent postviral lung disease. In that context, we found that the development of this type of lung disease was associated with increased lung Trem2 (but not other Trem) mRNA levels based on gene expression microarray and real-time qPCR assay (Fig. 2, A and B; and Table S1). Moreover, the development of postviral lung disease at 49 dpi in WT mice was markedly attenuated in Trem2−/− mice. Thus, Trem2−/− mice showed marked decreases in lung inflammation and airway mucus production based on tissue staining (Fig. 2 C) as well as significantly decreased lung levels of the key cytokine Il13 mRNA, the predominant mucin Muc5ac mRNA, and the M2 markers Arg1 and Chi3l3 mRNA based on real-time qPCR assay (Fig. 2 D). Dap12−/− mice exhibited a similar inhibition of postviral disease (Fig. 2, C and D), consistent with the association of TREM-2 and DAP12 phenotype in other systems (Bouchon et al., 2000; Kaifu et al., 2003; Turnbull et al., 2006). In contrast, Trem1/3−/− mice manifested no significant difference in the development of chronic postviral disease (Fig. 2, C and D), perhaps divergent from the pro-inflammatory role of TREM-1 in other disease models (Bouchon et al., 2001a; Schenk et al., 2007; Klesney-Tait et al., 2013).
Affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.