The role of the mucosal immune response in protecting against acute infectious illness versus promoting chronic inflammatory disease must be better defined to understand and treat these conditions. To address this issue, we are pursuing evidence that lung macrophages efficiently infiltrate the airway mucosal epithelium and adjacent parenchyma to control acute respiratory viral infection, but if unchecked could also contribute to chronic airway disease after the infection is cleared. In support of this hypothesis, we have learned that lung macrophages near the airway (in mucosal and adjacent parenchymal locations) express the myeloid receptor TREM-2 as distinct cell-surface and soluble forms, and that each form can stimulate anti-apoptotic signaling in macrophages to allow for macrophage survival. Thus, we showed that cell-surface TREM-2 is increased during viral infection by the action of dsRNA and prevents macrophage apoptosis during acute viral illness, whereas soluble TREM-2 (sTREM-2) is increased after clearance of infection by the actions of IL-13 and DAP12 and prevents macrophage apoptosis to further increase IL-13 production and chronic post-viral disease. The findings suggest that macrophages can be protective during the acute immune response but inflammatory during the chronic immune response to respiratory viral infection based on new actions of the TREM-2 signaling pathway. Preliminary studies of humans show that respiratory viral infection and IL-13 can also increase cell-surface and soluble TREM-2 levels in human macrophages. We now aim to further define the role of macrophage TREM-2 in acute and chronic mucosal immune responses to respiratory viral infection. Critical questions include: how cell-surface and soluble TREM-2 levels are regulated in lung macrophages, and how cell-surface and soluble forms of TREM-2 control anti-apoptotic pathways, especially in macrophage populations near the airway epithelium. We propose that TREM-2 (particularly as the cell-surface form) is an integral component of mucosal immunity whereas an exaggerated level of TREM-2 (particularly as the soluble form) provides a feed-forward mechanism to drive an excessive type 2 immune response. Thus, the cell-surface form of TREM-2 could protect against acute viral infection but the soluble form could promote chronic post-viral disease. We will especially compare the regulation and function of cell-surface to soluble TREM-2 to develop the hypothesis that down-regulating soluble TREM-2 level might even enhance cell-surface TREM-2 level and thereby improve immune function at mucosal barriers. Based on our preliminary studies, we next aim to: (1) define how TREM-2 is expressed, focusing on the appearance of TREM-2 at the cell surface and the cleavage of cell-surface TREM-2 to soluble TREM-2 in macrophages; and (2) define how cell-surface and soluble TREM-2 signal to inhibit apoptosis in macrophages, focusing on any differences between the two forms of TREM-2 in activating downstream signal transduction.
Respiratory viral infections are leading causes of morbidity and mortality in the U.S. and worldwide. Moreover, there are no specific and effective treatments for the common types of respiratory viral infection and no means to prevent the subsequent acute illness and chronic disease that develop after this type of infection. The proposed studies aim to understand how the respiratory airway responds to viral infection and especially how a specific protein and specific cell type participate in this response as a guide to fixing this major public health problem.
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