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: Given the difficulties in monitoring apoptosis in vivo (e.g., we detected no active caspase-3 tissue staining at 49 dpi; unpublished data) we sought additional markers of sTREM-2 action during postviral lung disease. In that regard, we were able to establish that sTREM-2 treatment resulted in a time-dependent and selective increase in molecular pathways connected to cell survival and proliferation, e.g., ERK1/2 and MAPK14 phosphorylation but not AKT phosphorylation or BCL-2 induction (Fig. 9 A). The effect of sTREM-2 on phospho-ERK1/2 and phospho-MAPK formation was more pronounced in BMDMs from Trem2−/− mice compared with WT mice (Fig. 9 A), consistent with the enhanced effect of sTREM-2 on viability of BMDMs from Trem-2−/− compared with WT mice based on fold-change (Fig. 8 D). In translating these findings to the postviral model in vivo, we found that phospho-ERK1/2 immunostaining was markedly increased and co-localized to lung macrophages at 49 dpi compared with 5 dpi or SeV-UV control conditions in WT mice (Fig. 9 B). Moreover, the increase in phospho-ERK1/2 immunostaining was not detected at 49 dpi in Trem2−/− mice (Fig. 9 B). These results were consistent with increases in the numbers of total immune cells and macrophages in the lung at 49 dpi in WT mice, as well as marked inhibition of this cellular response at 49 dpi in Trem2−/− mice (Fig. 9 C). Together, these findings provide for a crucial regulatory role of TREM-2 in a feed-forward pathway that expands the M2 macrophage population and thereby promotes IL-13–dependent chronic lung 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.