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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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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.
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fig10: 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.

Mentions: This report identifies TREM-2 as a key component of an innate immune pathway for the pathogenesis of chronic lung disease. We use a postviral mouse model of this type of disease to show that: (1) during acute illness, viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action mediates a CSF-1–dependent cell survival signal that prevents macrophage apoptosis; (2) during chronic postviral disease, IL-13 and DAP12 signals promote increased expression and cleavage of TREM-2 from the cell surface to form sTREM-2 at increased levels in the lung; and (3) sTREM-2 is not inactive as previously thought, but is instead capable of promoting macrophage survival via antiapoptotic signals such as ERK1/2 activation. Together, these events allow for TREM-2 to participate in a feed forward mechanism to amplify the accumulation of macrophages in the lung. In the context of our previous work, the increased number of macrophages would be available to interact with iNKT cells and drive further IL-13 production thereby resulting in 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 (as diagrammed in Fig. 10). The scheme is consistent with our observation that TREM-2–deficient mice are markedly protected from the development of chronic lung disease as a long-term consequence of viral infection.


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)

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.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4419356&req=5

fig10: 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.
Mentions: This report identifies TREM-2 as a key component of an innate immune pathway for the pathogenesis of chronic lung disease. We use a postviral mouse model of this type of disease to show that: (1) during acute illness, viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action mediates a CSF-1–dependent cell survival signal that prevents macrophage apoptosis; (2) during chronic postviral disease, IL-13 and DAP12 signals promote increased expression and cleavage of TREM-2 from the cell surface to form sTREM-2 at increased levels in the lung; and (3) sTREM-2 is not inactive as previously thought, but is instead capable of promoting macrophage survival via antiapoptotic signals such as ERK1/2 activation. Together, these events allow for TREM-2 to participate in a feed forward mechanism to amplify the accumulation of macrophages in the lung. In the context of our previous work, the increased number of macrophages would be available to interact with iNKT cells and drive further IL-13 production thereby resulting in 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 (as diagrammed in Fig. 10). The scheme is consistent with our observation that TREM-2–deficient mice are markedly protected from the development of chronic lung disease as a long-term consequence of 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.

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