Aging-impaired filamentous actin polymerization signaling reduces alveolar macrophage phagocytosis of bacteria

Zhigang Li, Yang Jiao, Erica K. Fan, Melanie J. Scott, Yuehua Li, Song Li, Timothy R. Billiar, Mark A. Wilson, Xueyin Shi*, Jie Fan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

In elderly patients, bacterial infection often causes severe complications and sepsis. Compared to younger patients, older patients are more susceptible to sepsis caused by respiratory infection. Macrophage (Mf) phagocytosis of bacteria plays a critical role in the clearance of pathogens and the initiation of immune responses. It has been suggested that Mf exhibit age-related functional alterations, including reduced chemotaxis, phagocytosis, antibacterial defense, and the ability to generate reactive oxygen species. However, the mechanisms behind these changes remain unclear. The present study sought to determine changes in bacterial phagocytosis in aging alveolar Mf (AMf) and the underlying mechanisms. We show that bacteria initiate cytoskeleton remodeling in AMf through interaction with macrophage receptor with collagenous structure (MARCO), a bacterial scavenger receptor. This remodeling, in turn, promotes enhanced cell surface expression of MARCO and bacterial phagocytosis. We further demonstrate that Rac1-GTP mediates MARCO signaling and activates actin-related protein-2/3 complex, an F-actin nucleator, thereby inducing F-actin polymerization, filopodia formation, and increased cell surface expression of MARCO, all of which are essential for the execution of bacteria phagocytosis. However, AMf isolated from aging mice exhibit suppressed Rac1 mRNA and protein expression, which resulted in decreases in Rac1-GTP levels and actin-related protein-2/3 activation, as well as subsequent attenuation of F-actin polymerization, filopodia formation, and cell surface expression of MARCO. As a result, bacterial phagocytosis in aging AMf is decreased. This study highlights a previously unidentified mechanism by which aging impairs Mf phagocytosis of bacteria. Targeting these pathways may improve outcomes of bacterial infection in elderly patients.

Original languageEnglish
Pages (from-to)3176-3186
Number of pages11
JournalJournal of Immunology
Volume199
Issue number9
DOIs
StatePublished - 1 Nov 2017
Externally publishedYes

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