CoChat
Sign Up
Cited by 207Inflammation biomarkers and pathwaysImmune Response and InflammationAsthma and respiratory diseases

The DOI matches its Crossref record; 40 of the 41 references it cites were found in a registry or an index.

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

Open access
Wu, Kangyun, Byers, Derek E., Jin, Xiaohua, Agapov, Eugene, Alexander-Brett, Jennifer, Patel, Anand C., Cella, Marina, Gilfilan, Susan, Colonna, Marco, Kober, Daniel L., Brett, Tom J., Holtzman, Michael J.·2015·Journal of Experimental Medicine
DOI 10.1084/jem.20141732PMC PMC4419356
Open this paper in CoChat — free account

Abstract

Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13-dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5-12 d after inoculation). 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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1084/jem.20141732

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1. Effect of macrophage deficiency on postviral lung disease. (A) Lung levels of total cells, tissue monocytes (tissue monos), interstitial macrophages (interstitial macs), and alveolar macrophages (alveolar macs) for wt/wt and wt/opT mice at 5 dpi with SeV or UV-inactivated SeV (SeV-UV) determined by flow cytometry staining with fluorescent bead-based quantitation. (B) For conditions in (A), corresponding values for 49 dpi. (C) Representative photomicrographs of lung sections stained with PAS plus hematoxylin, immunostained for MUC5AC and counterstained with hematoxylin, or immunostained for IL-13 and counterstained with DAPI. Bars, 200 µm. (D) Lung levels of Il13, Muc5ac, Arg1, and Chi3l3 mRNA in wt/wt and wt/opT mice at 49 dpi with SeV or SeV-UV. For A, B, and D, * represents a significant increase from SeV-UV, and ** represents a significant decrease from corresponding wt/wt control value. All experimental data were verified in at least three independent experiments.
Figure 1. Effect of macrophage deficiency on postviral lung disease. (A) Lung levels of total cells, tissue monocytes (tissue monos), interstitial macrophages (interstitial macs), and alveolar macrophages (alveolar macs) for wt/wt and wt/opT mice at 5 dpi with SeV or UV-inactivated SeV (SeV-UV) determined by flow cytometry staining with fluorescent bead-based quantitation. (B) For conditions in (A), corresponding values for 49 dpi. (C) Representative photomicrographs of lung sections stained with PAS plus hematoxylin, immunostained for MUC5AC and counterstained with hematoxylin, or immunostained for IL-13 and counterstained with DAPI. Bars, 200 µm. (D) Lung levels of Il13, Muc5ac, Arg1, and Chi3l3 mRNA in wt/wt and wt/opT mice at 49 dpi with SeV or SeV-UV. For A, B, and D, * represents a significant increase from SeV-UV, and ** represents a significant decrease from corresponding wt/wt control value. All experimental data were verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 2. 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.
Figure 2. 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.CC BY-NC-SA · PubMed Central
Figure 3. Similarity of acute illness after viral infection in WT and knockout mice. (A) Body weights in WT, Trem2−/−, Dap12−/−, and Trem1/3−/− mice at the indicated dpi. (B) Viral titers assessed by real-time qPCR assay for SeV N gene RNA in lungs of indicated mouse strains at 5 and 8 dpi. For A and B, values represent mean ± SEM for 4–7 mice. (C) Representative photomicrographs SeV immunostaining in lung sections from WT and Trem2−/− mice at 0–8 dpi. (D) Representative photomicrographs of hematoxylin and eosin staining of lung sections from indicated mouse strains at 5 dpi. Each section contains an area of bronchiolitis with inflammatory cells surrounding an airway and adjacent blood vessel. Bar, 200 µm. All experimental data were verified in at least three independent experiments.
Figure 3. Similarity of acute illness after viral infection in WT and knockout mice. (A) Body weights in WT, Trem2−/−, Dap12−/−, and Trem1/3−/− mice at the indicated dpi. (B) Viral titers assessed by real-time qPCR assay for SeV N gene RNA in lungs of indicated mouse strains at 5 and 8 dpi. For A and B, values represent mean ± SEM for 4–7 mice. (C) Representative photomicrographs SeV immunostaining in lung sections from WT and Trem2−/− mice at 0–8 dpi. (D) Representative photomicrographs of hematoxylin and eosin staining of lung sections from indicated mouse strains at 5 dpi. Each section contains an area of bronchiolitis with inflammatory cells surrounding an airway and adjacent blood vessel. Bar, 200 µm. All experimental data were verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 4. Induction and function of TREM-2 in lung macrophages during postviral lung disease. (A) Representative photomicrographs of TREM-2 plus F4/80 or Mac-3 immunostaining of lung sections from WT mice at 49 dpi with SeV or SeV-UV. Bar, 200 µm. (B) Representative photomicrographs of F4/80 plus IL-13 immunostaining of lung sections from WT and Trem2−/− mice at 49 dpi with SeV-UV or SeV. Bar, 200 µm. (C) Levels of Il13, Arg1, and Chi3l3 mRNA in FACS-purified tissue monos, interstitial macs, and alveolar macs from WT and Trem2−/− mice at 49 dpi with SeV or SeV-UV. Each value represents mean ± SEM for five mice and is representative of three experiments. * represents a significant increase from corresponding SeV-UV in WT value, and ** represents a significant decrease from corresponding SeV in WT value. All experimental data were verified in at least three independent experiments.
Figure 4. Induction and function of TREM-2 in lung macrophages during postviral lung disease. (A) Representative photomicrographs of TREM-2 plus F4/80 or Mac-3 immunostaining of lung sections from WT mice at 49 dpi with SeV or SeV-UV. Bar, 200 µm. (B) Representative photomicrographs of F4/80 plus IL-13 immunostaining of lung sections from WT and Trem2−/− mice at 49 dpi with SeV-UV or SeV. Bar, 200 µm. (C) Levels of Il13, Arg1, and Chi3l3 mRNA in FACS-purified tissue monos, interstitial macs, and alveolar macs from WT and Trem2−/− mice at 49 dpi with SeV or SeV-UV. Each value represents mean ± SEM for five mice and is representative of three experiments. * represents a significant increase from corresponding SeV-UV in WT value, and ** represents a significant decrease from corresponding SeV in WT value. All experimental data were verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 5. Regulation of cell surface and intracellular TREM-2 levels during viral replication and postviral lung disease. (A) Representative histograms from FACS analysis of TREM-2 immunostaining for tissue monos, interstitial macs, and alveolar macs from lungs of mice at 5 or 49 dpi with SeV-UV or SeV. (B) Corresponding MFI values for cell surface TREM-2 levels on tissue monos at the indicated dpi based on analysis conditions in A. (C) Representative cytograms from flow cytometry analysis of cell surface TREM-2 immunostaining for BMDMs at 0–3 dpi with GFP-expressing SeV (SeV-GFP). (D) Corresponding MFI values for cell surface TREM-2 and SeV-GFP for conditions in C. (E) Representative histograms for flow cytometry analysis of cell surface and intracellular TREM-2 immunostaining for BMDMs with indicated conditions. (F) Western blotting of TREM-2 in BMDMs at 2 dpi with SeV (MOI 0–10). (G) ELISA of cellular TREM-2 and sTREM-2 in BMDMs at 2 dpi with SeV for indicated MOI or with SeV at MOI 10 for 0–3 dpi. * represents a significant increase from corresponding control at MOI 0 and 0 dpi and Ø represents an undetectable level of sTREM-2. (H) Trem2 mRNA level in BMDMs with SeV at MOI 1 and 10 for 0–1 dpi. All experimental data verified in at least three independent experiments.
Figure 5. Regulation of cell surface and intracellular TREM-2 levels during viral replication and postviral lung disease. (A) Representative histograms from FACS analysis of TREM-2 immunostaining for tissue monos, interstitial macs, and alveolar macs from lungs of mice at 5 or 49 dpi with SeV-UV or SeV. (B) Corresponding MFI values for cell surface TREM-2 levels on tissue monos at the indicated dpi based on analysis conditions in A. (C) Representative cytograms from flow cytometry analysis of cell surface TREM-2 immunostaining for BMDMs at 0–3 dpi with GFP-expressing SeV (SeV-GFP). (D) Corresponding MFI values for cell surface TREM-2 and SeV-GFP for conditions in C. (E) Representative histograms for flow cytometry analysis of cell surface and intracellular TREM-2 immunostaining for BMDMs with indicated conditions. (F) Western blotting of TREM-2 in BMDMs at 2 dpi with SeV (MOI 0–10). (G) ELISA of cellular TREM-2 and sTREM-2 in BMDMs at 2 dpi with SeV for indicated MOI or with SeV at MOI 10 for 0–3 dpi. * represents a significant increase from corresponding control at MOI 0 and 0 dpi and Ø represents an undetectable level of sTREM-2. (H) Trem2 mRNA level in BMDMs with SeV at MOI 1 and 10 for 0–1 dpi. All experimental data verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 6. Effect of cellular TREM-2 on macrophage apoptosis during acute viral infection. (A) Flow cytometry analysis of lung levels of total cells, tissue monos, and neutrophils (SSChighLy6G+) for WT and Trem2−/− mice at 0–5 dpi with SeV. (B) Ccl2 and Cx3cl1 mRNA levels in WT and Trem2−/− mice at 0–5 dpi. For A and B, values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi and ** a significant decrease from corresponding WT mice. (C) Representative cytograms for flow cytometry analysis of levels of CD45.2+ tissue monos in WT and Trem2−/− mice at 3 dpi after CD45.2 WT and Trem2−/− BMDMs were introduced into CD45.1 WT mice at 0 dpi. (D) Representative photomicrographs of active caspase-3 and Mac-3 immunostaining of lung sections from WT and Trem2−/− mice at 8 dpi. Arrows indicate cells with double-positive immunostaining. Bar, 200 µm. (E) Quantification of analysis in (D). Values represent mean ± SEM for 12 randomly selected fields of lung sections from 3 mice, and ** represents a significant increase from corresponding WT mice. (F) Representative photomicrographs of active caspase-3 and SeV immunostaining of lung sections from WT and Trem2−/− mice at 5 dpi. Arrows indicate cells with active caspase-3+ immunostaining. Bar, 200 µm. (G) Lung levels of Csf1 mRNA for WT and Trem2−/− mice at indicated dpi. (H) Corresponding lung levels of CSF-1 for conditions in (G). For G and H, values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi. (I) Flow cytometry analysis of propidium iodide staining of BMDMs from WT and Trem2−/− mice cultured with or without CSF-1 for 1 d. (J) Levels of Annexin V immunostaining in PI– cells for culture conditions in (I). Values represent mean ± SEM for 6 randomly selected fields of replicate wells, and * represents a significant increase from (+) CSF-1, and ** a significant increase from corresponding WT mice. (K) Western blot levels of active caspase-3 for culture conditions in I. All experimental data were verified in at least three independent experiments.
Figure 6. Effect of cellular TREM-2 on macrophage apoptosis during acute viral infection. (A) Flow cytometry analysis of lung levels of total cells, tissue monos, and neutrophils (SSChighLy6G+) for WT and Trem2−/− mice at 0–5 dpi with SeV. (B) Ccl2 and Cx3cl1 mRNA levels in WT and Trem2−/− mice at 0–5 dpi. For A and B, values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi and ** a significant decrease from corresponding WT mice. (C) Representative cytograms for flow cytometry analysis of levels of CD45.2+ tissue monos in WT and Trem2−/− mice at 3 dpi after CD45.2 WT and Trem2−/− BMDMs were introduced into CD45.1 WT mice at 0 dpi. (D) Representative photomicrographs of active caspase-3 and Mac-3 immunostaining of lung sections from WT and Trem2−/− mice at 8 dpi. Arrows indicate cells with double-positive immunostaining. Bar, 200 µm. (E) Quantification of analysis in (D). Values represent mean ± SEM for 12 randomly selected fields of lung sections from 3 mice, and ** represents a significant increase from corresponding WT mice. (F) Representative photomicrographs of active caspase-3 and SeV immunostaining of lung sections from WT and Trem2−/− mice at 5 dpi. Arrows indicate cells with active caspase-3+ immunostaining. Bar, 200 µm. (G) Lung levels of Csf1 mRNA for WT and Trem2−/− mice at indicated dpi. (H) Corresponding lung levels of CSF-1 for conditions in (G). For G and H, values represent mean ± SEM for 5 mice, and * represents a significant increase from 0 dpi. (I) Flow cytometry analysis of propidium iodide staining of BMDMs from WT and Trem2−/− mice cultured with or without CSF-1 for 1 d. (J) Levels of Annexin V immunostaining in PI– cells for culture conditions in (I). Values represent mean ± SEM for 6 randomly selected fields of replicate wells, and * represents a significant increase from (+) CSF-1, and ** a significant increase from corresponding WT mice. (K) Western blot levels of active caspase-3 for culture conditions in I. All experimental data were verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 7. Effect of IL-13 on production of sTREM-2. (A) Lung levels of TREM-2 determined by ELISA at 5 or 49 dpi with SeV or SeV-UV. Values represent mean ± SEM for 5 mice, and * represents a significant increase from corresponding SeV-UV mice. (B) Representative histograms from flow cytometry analysis of cell surface TREM-2 on BMDMs treated with or without IL-13 (20 ng/ml) or IgG control for 1–3 d. (C) Representative histograms from flow cytometry analysis of cell surface TREM-2 on BMDMs treated with or without IL-13, IL-4, IL-5, or IL-9 (20 ng/ml) or IgG control for 1 d. (D) Levels of cellular and sTREM-2 in BMDMs obtained from WT and Dap12−/− mice and cultured with IL-13 for 1–3 d post-administration (dpa) as in B. Values represent mean ± SEM for 3 replicate wells, and * represents a significant increase from 0 dpa and ** a significant decrease from corresponding WT cells. (E) Lung levels of TREM-2 in WT and Dap12−/− mice at 49 dpi. Values represent mean ± SEM for 5 mice, and * represents a significant increase from SeV-UV and ** a significant decrease from corresponding WT mice. All experimental data were verified in at least three independent experiments.
Figure 7. Effect of IL-13 on production of sTREM-2. (A) Lung levels of TREM-2 determined by ELISA at 5 or 49 dpi with SeV or SeV-UV. Values represent mean ± SEM for 5 mice, and * represents a significant increase from corresponding SeV-UV mice. (B) Representative histograms from flow cytometry analysis of cell surface TREM-2 on BMDMs treated with or without IL-13 (20 ng/ml) or IgG control for 1–3 d. (C) Representative histograms from flow cytometry analysis of cell surface TREM-2 on BMDMs treated with or without IL-13, IL-4, IL-5, or IL-9 (20 ng/ml) or IgG control for 1 d. (D) Levels of cellular and sTREM-2 in BMDMs obtained from WT and Dap12−/− mice and cultured with IL-13 for 1–3 d post-administration (dpa) as in B. Values represent mean ± SEM for 3 replicate wells, and * represents a significant increase from 0 dpa and ** a significant decrease from corresponding WT cells. (E) Lung levels of TREM-2 in WT and Dap12−/− mice at 49 dpi. Values represent mean ± SEM for 5 mice, and * represents a significant increase from SeV-UV and ** a significant decrease from corresponding WT mice. All experimental data were verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 8. Effect of sTREM-2 on macrophage apoptosis. (A) Representative photomicrographs of immunostaining for recombinant sTREM-2 after incubation with BMDMs for 30 min with and without cell permeabilization with saponin. Bar, 100 µm. (B) Levels of Arg1 and Chi3l3 mRNA in BMDMs obtained from Trem2−/− and WT mice and then cultured with sTREM-2 (0–200 ng/ml) or IL-13 (20 ng/ml) for 1 d. Values represent mean ± SEM for 3 replicate wells, and * represents a significant increase from no treatment control (0 ng/ml). (C) Representative photomicrographs of sTREM-2–treated BMDMs cultured in 15% l-cell conditioned medium for 7 d. Bar = 200 µm. (D) XTT assay for BMDMs obtained from WT, Trem2−/−, and Dap12−/− mice and then cultured with sTREM-2 (0–200 ng/ml) for 2 d after CSF-1 withdrawal. Values represent mean ± SEM for 3 replicate wells, and * represents a significant increase from corresponding untreated control cells. (E) XTT assay of BMDMs from WT mice cultured with native (unheated) or denatured (heated) sTREM-2 (0–200 ng/ml) with culture conditions in D. * represents a significant increase from corresponding untreated control cells. (F) Flow cytometry analysis of propidium iodide staining of BMDMs obtained from WT, Trem2−/−, and Dap12−/− mice and cultured with sTREM-2 (0–200 ng/ml) with or without CSF-1 for 1 d. (G) Western blot levels of active caspase-3 for culture conditions in F. (H) Flow cytometry analysis of BrdU-labeling of BMDMs from Trem2−/− mice for culture conditions in F. All experimental data were verified in at least three independent experiments.
Figure 8. Effect of sTREM-2 on macrophage apoptosis. (A) Representative photomicrographs of immunostaining for recombinant sTREM-2 after incubation with BMDMs for 30 min with and without cell permeabilization with saponin. Bar, 100 µm. (B) Levels of Arg1 and Chi3l3 mRNA in BMDMs obtained from Trem2−/− and WT mice and then cultured with sTREM-2 (0–200 ng/ml) or IL-13 (20 ng/ml) for 1 d. Values represent mean ± SEM for 3 replicate wells, and * represents a significant increase from no treatment control (0 ng/ml). (C) Representative photomicrographs of sTREM-2–treated BMDMs cultured in 15% l-cell conditioned medium for 7 d. Bar = 200 µm. (D) XTT assay for BMDMs obtained from WT, Trem2−/−, and Dap12−/− mice and then cultured with sTREM-2 (0–200 ng/ml) for 2 d after CSF-1 withdrawal. Values represent mean ± SEM for 3 replicate wells, and * represents a significant increase from corresponding untreated control cells. (E) XTT assay of BMDMs from WT mice cultured with native (unheated) or denatured (heated) sTREM-2 (0–200 ng/ml) with culture conditions in D. * represents a significant increase from corresponding untreated control cells. (F) Flow cytometry analysis of propidium iodide staining of BMDMs obtained from WT, Trem2−/−, and Dap12−/− mice and cultured with sTREM-2 (0–200 ng/ml) with or without CSF-1 for 1 d. (G) Western blot levels of active caspase-3 for culture conditions in F. (H) Flow cytometry analysis of BrdU-labeling of BMDMs from Trem2−/− mice for culture conditions in F. All experimental data were verified in at least three independent experiments.CC BY-NC-SA · PubMed Central
Figure 9. 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.
Figure 9. 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.CC BY-NC-SA · PubMed Central
Figure 10. Scheme for regulation and function of TREM-2 in chronic postviral lung disease. Major steps include: (1) early activation of lung macrophages in which viral replication increases TREM-2 at the cell surface; (2) cleavage of TREM-2 from the cell surface to form sTREM-2 in a process that is up-regulated by IL-13 and DAP12; (3) sTREM-2 actions to prevent apoptosis in association with increased ERK1/2 activation and thereby allow for amplified macrophage interaction with iNKT cells and consequent IL-13 production; and (4) IL-13–dependent differentiation of the macrophage population toward an M2 pattern of gene expression (including Arg1 and Chi3l3) and differentiation of an airway progenitor epithelial cell (APEC) niche to airway mucous cells (AMCs) as signatures of chronic lung disease.
Figure 10. Scheme for regulation and function of TREM-2 in chronic postviral lung disease. Major steps include: (1) early activation of lung macrophages in which viral replication increases TREM-2 at the cell surface; (2) cleavage of TREM-2 from the cell surface to form sTREM-2 in a process that is up-regulated by IL-13 and DAP12; (3) sTREM-2 actions to prevent apoptosis in association with increased ERK1/2 activation and thereby allow for amplified macrophage interaction with iNKT cells and consequent IL-13 production; and (4) IL-13–dependent differentiation of the macrophage population toward an M2 pattern of gene expression (including Arg1 and Chi3l3) and differentiation of an airway progenitor epithelial cell (APEC) niche to airway mucous cells (AMCs) as signatures of chronic lung disease.CC BY-NC-SA · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 41 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Wu, K., Byers, D. E., Jin, X., Agapov, E., Alexander-Brett, J., Patel, A. C., Cella, M., Gilfilan, S., Colonna, M., Kober, D. L., Brett, T. J., & Holtzman, M. J.
Affiliations
  • Washington University in St. Louis (US)
  • Pulmonary and Critical Care Medicine, Department of Medicine 1 , 2 , 3 , 4 , and 5
Corresponding author
Holtzman, Michael J.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2015-04-20
Volume
212
Issue
5
Pages
681-697
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20141732
PMC
PMC4419356
OpenAlex
W2111240640
Cited by
207
References
41
Citations by year
2026: 11 · 2025: 17 · 2024: 19 · 2023: 23 · 2022: 36 · 2021: 24 · 2020: 22 · 2019: 8 · 2018: 14 · 2017: 16 · 2016: 11 · 2015: 4
FWCI
7.33
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL119813, P01HL029594, R01HL073159, R01HL121791, P50HL084922, T32HL007317)
  • National Institute of Allergy and Infectious Diseases (U19-AI07048, U19AI070489)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
Keywords
TREM2, macrophage survival, macrophage apoptosis, Sendai virus, respiratory viral infections, IL-13, DAP12, M2 macrophages, Th2 immune response, airway mucus hypersecretion, innate immune activation
MeSH terms
Animals, Cell Survival, Immunity, Innate, Lung Diseases, Membrane Glycoproteins, Respirovirus Infections, Receptors, Immunologic, Virus Replication, Macrophages, Alveolar, Apoptosis, Mice, Knockout, Interleukin-13, Sendai virus, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review