Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice

Wong, Christine; Smith, Candice A.; Sakamoto, Koji; Kaminski, Naftali; Koff, Jonathan L.; Goldstein, Daniel R.

doi:10.4049/jimmunol.1700397

Cited by 158 publications

(146 citation statements)

References 32 publications

(54 reference statements)

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“…We found that lung macrophages from old mice were defective in their ability to ingest dead cells ( Figure 2B). 29,30 Also, we observed that IL-6 is increased in lungs from old mice and while we do not know the cellular source, our data suggest that the increase may be due to activated macrophages in lungs. 29,30 Also, we observed that IL-6 is increased in lungs from old mice and while we do not know the cellular source, our data suggest that the increase may be due to activated macrophages in lungs.…”

Section: Discussionmentioning

confidence: 53%

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell‐induced MerTK cleavage

et al. 2019

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Inflammation‐resolution is mediated by the balance between specialized pro‐resolving mediators (SPMs) like resolvin D1 (RvD1) and pro‐inflammatory factors, like leukotriene B4 (LTB4). A key cellular process of inflammation‐resolution is efferocytosis. Aging is associated with defective inflammation‐resolution and the accumulation of pro‐inflammatory senescent cells (SCs). Therefore, understanding mechanism(s) that underpin this impairment is a critical gap. Here, using a model of hind limb ischemia‐reperfusion (I/R) remote lung injury, we present evidence that aging is associated with heightened inflammation, impaired SPM:LT ratio, defective efferocytosis, and a decrease in MerTK levels in injured lungs. Treatment with RvD1 mitigated I/R lung injury in aging, promoted efferocytosis, and prevented the decrease of MerTK in injured lungs from old mice. Old MerTK cleavage‐resistant mice (MerTKCR) exhibited less neutrophils or polymorpho nuclear cells infiltration and had improved efferocytosis compared with old WT controls. Mechanistically, macrophages that were treated with conditioned media (CM) from senescent cells had increased MerTK cleavage, impaired efferocytosis, and a defective RvD1:LTB4 ratio. Macrophages from MerTKCR mice were resistant to CM‐induced efferocytosis defects and had an improved RvD1:LTB4 ratio. RvD1‐stimulated macrophages prevented CM‐induced MerTK cleavage and promoted efferocytosis. Together, these data suggest a new mechanism and a potential therapy to promote inflammation‐resolution and efferocytosis in aging.

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Section: Discussionmentioning

confidence: 53%

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell‐induced MerTK cleavage

et al. 2019

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“…The utility of the mice to study how aging affects influenza viral lung infection is somewhat controversial. At least five studies of either C57BL/6 mice or BALB/c mice report that aged mice (16–24 months old) display enhanced morbidity or mortality during influenza A virus (IAV) infection compared to young mice (2–4 months old), similar to humans (Steeg, ; Stout‐Delgado, Vaughan, Shirali, Jaramillo, & Harrod, ; Toapanta & Ross, ; Wong et al, ; Zhao, Zhao, Legge, & Perlman, ). In contrast, two studies of aged C57BL/6 mice (16–30 months old) report that aged mice exhibit reduced mortality during IAV infection compared to young mice (2–4 months old; Lu et al, ; Pillai et al, ).…”

Section: Introduction Results and Discussionmentioning

confidence: 99%

Influenza virus inoculum volume is critical to elucidate age‐dependent mortality in mice

et al. 2019

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The elderly exhibit increased mortality to influenza viral infection for unclear reasons. Mice are frequently used to model how aging impacts disease. Several studies have shown that aged mice exhibit an increased mortality to influenza virus, but two recent studies demonstrated the opposite. These two studies administered the virus intranasally in 20 µL, whereas the other studies used a viral inoculum in at least 30 µL. To determine whether the volume of the inoculum could explain the conflicting reports, we infected young and aged mice via intranasal instillation of 40 µL or 20 µL containing 1 x 104 plaque‐forming units (PFU) of H1N1 influenza virus. We found that intranasal administration of 40 µL but not 20 µL of inoculum resulted in age‐dependent mortality in mice. Compared to aged mice infected with 40 µL inoculum, those infected with 20 µL inoculum showed reduced levels of live virus and IFN‐β in the lung 3 days postinfection. Furthermore, aged mice administered 40 µL of Evans blue intranasally displayed increased dye retention in their bronchoalveolar lavage fluid compared to those administered 20 µL of Evans blue. Our data demonstrate that the inoculating volume of virus is critical for adequate delivery of influenza virus to the lung and thus for efficient infection of aged mice. These findings shed light on discrepant results in the literature regarding aged mice and influenza infection, and establish that mice can be used to examine how aging impacts the response to this biomedically important infection.

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“…Macrophages maintain environmental homeostasis through the removal of apoptotic cells and debris. As such, AMs are also important during the tissue repair phase that follows an active infection by IAV through the efferocytosis of dying epithelia and neutrophils (77). Epithelial cell proliferation and repair after influenza is promoted by AM products such as hepatocyte growth factor (78), TGF-α (79), and TGF-β (80).…”

Section: Epithelial-resident Leukocyte Crosstalk During Early Iav Infmentioning

confidence: 99%

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

et al. 2020

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The primary function of the respiratory system of gas exchange renders it vulnerable to environmental pathogens that circulate in the air. Physical and cellular barriers of the respiratory tract mucosal surface utilize a variety of strategies to obstruct microbe entry. Physical barrier defenses including the surface fluid replete with antimicrobials, neutralizing immunoglobulins, mucus, and the epithelial cell layer with rapidly beating cilia form a near impenetrable wall that separates the external environment from the internal soft tissue of the host. Resident leukocytes, primarily of the innate immune branch, also maintain airway integrity by constant surveillance and the maintenance of homeostasis through the release of cytokines and growth factors. Unfortunately, pathogens such as influenza virus and Streptococcus pneumoniae require hosts for their replication and dissemination, and prey on the respiratory tract as an ideal environment causing severe damage to the host during their invasion. In this review, we outline the host-pathogen interactions during influenza and post-influenza bacterial pneumonia with a focus on interand intra-cellular crosstalk important in pulmonary immune responses.

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Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice

Cited by 158 publications

References 32 publications

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell‐induced MerTK cleavage

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell‐induced MerTK cleavage

Influenza virus inoculum volume is critical to elucidate age‐dependent mortality in mice

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

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