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TREM-2 promotes macrophage survival and lung disease after respiratory viral infection.

Wu K, Byers DE, Jin X, Agapov E, Alexander-Brett J, Patel AC, Cella M, Gilfilan S, Colonna M, Kober DL, Brett TJ, Holtzman MJ - J. Exp. Med. (2015)

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.

View Article: PubMed Central - HTML - PubMed

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.

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Effect of TREM-2 deficiency on apoptosis signaling pathway. (A) Western blot levels of indicated cell survival proteins in BMDMs cultured from WT and Trem22/2 mice after treatment with mouse sTREM-2 (200 ng/ml) for 0–24 h. (B) Representative photomicrographs of phospho-ERK1/2 (p-ERK) and Mac-3 immunostaining with DAPI counterstaining of lung sections from WT and Trem22/2 mice at 5 or 49 dpi with SeV or SeV-UV. Arrows indicate cells with double-positive immunostaining. Bar, 200 µm. (C) Flow cytometry analysis of lung levels of total cells and tissue monos for WT and Trem22/2 mice at 0 and 49 dpi. Values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi and ** a significant decrease from corresponding WT mice. Values at 0 dpi were no different than those for SeV-UV (49 dpi). All experimental data were verified in at least three independent experiments.
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fig9: Effect of TREM-2 deficiency on apoptosis signaling pathway. (A) Western blot levels of indicated cell survival proteins in BMDMs cultured from WT and Trem22/2 mice after treatment with mouse sTREM-2 (200 ng/ml) for 0–24 h. (B) Representative photomicrographs of phospho-ERK1/2 (p-ERK) and Mac-3 immunostaining with DAPI counterstaining of lung sections from WT and Trem22/2 mice at 5 or 49 dpi with SeV or SeV-UV. Arrows indicate cells with double-positive immunostaining. Bar, 200 µm. (C) Flow cytometry analysis of lung levels of total cells and tissue monos for WT and Trem22/2 mice at 0 and 49 dpi. Values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi and ** a significant decrease from corresponding WT mice. Values at 0 dpi were no different than those for SeV-UV (49 dpi). All experimental data were verified in at least three independent experiments.

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.


TREM-2 promotes macrophage survival and lung disease after respiratory viral infection.

Wu K, Byers DE, Jin X, Agapov E, Alexander-Brett J, Patel AC, Cella M, Gilfilan S, Colonna M, Kober DL, Brett TJ, Holtzman MJ - J. Exp. Med. (2015)

Effect of TREM-2 deficiency on apoptosis signaling pathway. (A) Western blot levels of indicated cell survival proteins in BMDMs cultured from WT and Trem22/2 mice after treatment with mouse sTREM-2 (200 ng/ml) for 0–24 h. (B) Representative photomicrographs of phospho-ERK1/2 (p-ERK) and Mac-3 immunostaining with DAPI counterstaining of lung sections from WT and Trem22/2 mice at 5 or 49 dpi with SeV or SeV-UV. Arrows indicate cells with double-positive immunostaining. Bar, 200 µm. (C) Flow cytometry analysis of lung levels of total cells and tissue monos for WT and Trem22/2 mice at 0 and 49 dpi. Values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi and ** a significant decrease from corresponding WT mice. Values at 0 dpi were no different than those for SeV-UV (49 dpi). All experimental data were verified in at least three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig9: Effect of TREM-2 deficiency on apoptosis signaling pathway. (A) Western blot levels of indicated cell survival proteins in BMDMs cultured from WT and Trem22/2 mice after treatment with mouse sTREM-2 (200 ng/ml) for 0–24 h. (B) Representative photomicrographs of phospho-ERK1/2 (p-ERK) and Mac-3 immunostaining with DAPI counterstaining of lung sections from WT and Trem22/2 mice at 5 or 49 dpi with SeV or SeV-UV. Arrows indicate cells with double-positive immunostaining. Bar, 200 µm. (C) Flow cytometry analysis of lung levels of total cells and tissue monos for WT and Trem22/2 mice at 0 and 49 dpi. Values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi and ** a significant decrease from corresponding WT mice. Values at 0 dpi were no different than those for SeV-UV (49 dpi). All experimental data were verified in at least three independent experiments.
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.

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.

View Article: PubMed Central - HTML - PubMed

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
Related in: MedlinePlus