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Isolation and In Vitro Culture of Murine and Human Alveolar Macrophages
Published on: April 20, 2018
Alveolar macrophage-derived extracellular vesicles inhibit endosomal fusion of influenza virus
Daniel J Schneider1, Katherine A Smith1, Catrina E Latuszek1
1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Abstract:
Alveolar macrophages (AMs) and epithelial cells (ECs) are the lone resident lung cells positioned to respond to pathogens at early stages of infection. Extracellular vesicles (EVs) are important vectors of paracrine signaling implicated in a range of (patho)physiologic contexts. Here we demonstrate that AMs, but not ECs, constitutively secrete paracrine activity localized to EVs which inhibits influenza infection of ECs in vitro and in vivo. AMs exposed to cigarette smoke extract lost the inhibitory activity of their secreted EVs. Influenza strains varied in their susceptibility to inhibition by AM-EVs. Only those exhibiting early endosomal escape and high pH of fusion were inhibited via a reduction in endosomal pH. By contrast, strains exhibiting later endosomal escape and lower fusion pH proved resistant to inhibition. These results extend our understanding of how resident AMs participate in host defense and have broader implications in the defense and treatment of pathogens internalized within endosomes.
Insights
Resident alveolar macrophages (AMs) secrete extracellular vesicles (EVs) that inhibit influenza infection in lung epithelial cells (ECs). Cigarette smoke exposure impairs this protective AM-EV function, affecting host defense.
Area of Science:
- Immunology
- Cell Biology
- Respiratory Medicine
Background:
- Alveolar macrophages (AMs) and epithelial cells (ECs) are key lung cells involved in early host defense against pathogens.
- Extracellular vesicles (EVs) mediate intercellular communication and play roles in various physiological and pathological processes.
Purpose of the Study:
- To investigate the role of AM-secreted EVs in influenza infection.
- To determine the impact of cigarette smoke on AM-EV function.
- To elucidate the mechanism by which AM-EVs inhibit influenza infection.
Main Methods:
- In vitro and in vivo experiments using cultured lung cells and animal models.
- Analysis of EV secretion by AMs and ECs.
- Exposure of AMs to cigarette smoke extract.
- Characterization of influenza strain susceptibility to AM-EVs based on endosomal escape and fusion pH.
Main Results:
- AMs, but not ECs, constitutively secrete EVs with paracrine activity that inhibits influenza infection.
- Exposure of AMs to cigarette smoke extract abrogated the inhibitory function of their secreted EVs.
- Influenza strains with early endosomal escape and high fusion pH were susceptible to AM-EV inhibition via endosomal acidification.
- Strains with later endosomal escape and lower fusion pH were resistant to AM-EVs.
Conclusions:
- AM-derived EVs are crucial for innate lung immunity against influenza by modulating endosomal pH.
- Cigarette smoke compromises this protective mechanism, potentially increasing susceptibility to viral infections.
- Understanding AM-EVs and their modulation by environmental factors offers insights into host defense and therapeutic strategies for endosomally-internalized pathogens.
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