TY - JOUR
T1 - TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
AU - Wu, Kangyun
AU - Byers, Derek E.
AU - Jin, Xiaohua
AU - Agapov, Eugene
AU - Alexander-Brett, Jennifer
AU - Patel, Anand C.
AU - Cella, Marina
AU - Gilfilan, Susan
AU - Colonna, Marco
AU - Kober, Daniel L.
AU - Brett, Tom J.
AU - Holtzman, Michael J.
N1 - Publisher Copyright:
© 2015 Wu et al.
PY - 2015/5/4
Y1 - 2015/5/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84940763775&partnerID=8YFLogxK
U2 - 10.1084/jem.20141732
DO - 10.1084/jem.20141732
M3 - Article
C2 - 25897174
AN - SCOPUS:84940763775
SN - 0022-1007
VL - 212
SP - 681
EP - 697
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -