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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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Induction and function of Trem2 gene expression during postviral lung disease. (A) Gene expression microarray analysis of mRNA from lungs of mice at 3 and 49 dpi with SeV (105 pfu) or SeV-UV. Scatter plot depicts log2 normalized gene expression. Each symbol represents the expression value for an individual gene with the top 20 differentially expressed genes colored red and annotated in black, and others colored gray. Genes encoding Trem family members and Dap12 are colored red if significantly increased, blue if decreased, or white if unchanged, and are annotated in red. (B) Lung levels of Trem1, Trem2, and Il13 mRNA at indicated dpi with SeV. * represents a significant increase from (–) SeV control value. Values at 0 dpi were no different than those for SeV-UV 0–49 dpi. (C) Representative photomicrographs of PAS and Muc5ac staining of lung sections from WT, Trem2−/−, Dap12−/−, and Trem1/3−/− mice at SeV p.i. day 49. Bar, 200 µm. (D) Corresponding lung levels of Il13, Muc5ac, Arg1, and Chi3l3 mRNA for conditions in (A). * represents a significant increase from SeV-UV mice and ** a significant decrease from corresponding WT control mice. All experimental data were verified in at least three independent experiments.
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fig2: Induction and function of Trem2 gene expression during postviral lung disease. (A) Gene expression microarray analysis of mRNA from lungs of mice at 3 and 49 dpi with SeV (105 pfu) or SeV-UV. Scatter plot depicts log2 normalized gene expression. Each symbol represents the expression value for an individual gene with the top 20 differentially expressed genes colored red and annotated in black, and others colored gray. Genes encoding Trem family members and Dap12 are colored red if significantly increased, blue if decreased, or white if unchanged, and are annotated in red. (B) Lung levels of Trem1, Trem2, and Il13 mRNA at indicated dpi with SeV. * represents a significant increase from (–) SeV control value. Values at 0 dpi were no different than those for SeV-UV 0–49 dpi. (C) Representative photomicrographs of PAS and Muc5ac staining of lung sections from WT, Trem2−/−, Dap12−/−, and Trem1/3−/− mice at SeV p.i. day 49. Bar, 200 µm. (D) Corresponding lung levels of Il13, Muc5ac, Arg1, and Chi3l3 mRNA for conditions in (A). * represents a significant increase from SeV-UV mice and ** a significant decrease from corresponding WT control mice. All experimental data were verified in at least three independent experiments.

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).


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)

Induction and function of Trem2 gene expression during postviral lung disease. (A) Gene expression microarray analysis of mRNA from lungs of mice at 3 and 49 dpi with SeV (105 pfu) or SeV-UV. Scatter plot depicts log2 normalized gene expression. Each symbol represents the expression value for an individual gene with the top 20 differentially expressed genes colored red and annotated in black, and others colored gray. Genes encoding Trem family members and Dap12 are colored red if significantly increased, blue if decreased, or white if unchanged, and are annotated in red. (B) Lung levels of Trem1, Trem2, and Il13 mRNA at indicated dpi with SeV. * represents a significant increase from (–) SeV control value. Values at 0 dpi were no different than those for SeV-UV 0–49 dpi. (C) Representative photomicrographs of PAS and Muc5ac staining of lung sections from WT, Trem2−/−, Dap12−/−, and Trem1/3−/− mice at SeV p.i. day 49. Bar, 200 µm. (D) Corresponding lung levels of Il13, Muc5ac, Arg1, and Chi3l3 mRNA for conditions in (A). * represents a significant increase from SeV-UV mice and ** a significant decrease from corresponding WT control mice. All experimental data were verified in at least three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig2: Induction and function of Trem2 gene expression during postviral lung disease. (A) Gene expression microarray analysis of mRNA from lungs of mice at 3 and 49 dpi with SeV (105 pfu) or SeV-UV. Scatter plot depicts log2 normalized gene expression. Each symbol represents the expression value for an individual gene with the top 20 differentially expressed genes colored red and annotated in black, and others colored gray. Genes encoding Trem family members and Dap12 are colored red if significantly increased, blue if decreased, or white if unchanged, and are annotated in red. (B) Lung levels of Trem1, Trem2, and Il13 mRNA at indicated dpi with SeV. * represents a significant increase from (–) SeV control value. Values at 0 dpi were no different than those for SeV-UV 0–49 dpi. (C) Representative photomicrographs of PAS and Muc5ac staining of lung sections from WT, Trem2−/−, Dap12−/−, and Trem1/3−/− mice at SeV p.i. day 49. Bar, 200 µm. (D) Corresponding lung levels of Il13, Muc5ac, Arg1, and Chi3l3 mRNA for conditions in (A). * represents a significant increase from SeV-UV mice and ** a significant decrease from corresponding WT control mice. All experimental data were verified in at least three independent experiments.
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).

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