Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality

Abstract

Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral clearance or a pathological host immune response is unknown. Here, we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines CXCL1 and CXCL2 during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro . Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.

Tissue-resident CD8+T cells drive age-associated chronic lung sequelae following viral pneumonia

“…To investigate the short and long-term effects of aging on influenza disease severity, young (2 month old) and aged (21-22 month old) C57BL/6 mice were infected with influenza A virus (IAV; A/PR8/34 strain (PR8), Figure 1A). While 100% of young mice survived from intranasal infection with PR8, ∼50% of aged mice succumbed to the infection by day 12 (Figure 1B), which are consistent with previous reports that aged mice exhibited enhanced host mortality following primary influenza infection [22]. Aged mice that survived exhibited prolonged weight recovery, although their weight completely recovered by 20 days post infection (d.p.i.)…”

“…Neutrophil counts in the circulation exhibited a slight increase in aging relative to young as has been reported at 9 d.p.i. (Figure 1H) [22]. Further, there were more tissue-resident neutrophils and monocytes in the aged group at 9 d.p.i.…”

“…To confirm these lung histopathological data, we examined the presence of inflammatory monocytes and neutrophils, two major inflammatory cells that can cause pulmonary inflammation and tissue damage [22, 25]. To discern the anatomical location of the cell infiltrates, we examined the vascular and parenchymal fractions of the lungs through the injection of intravenous CD45 antibody (Ab) 5 min before sacrifice [26] (Figure 1G).…”

“…To this end, even though D b -NP T RM cells have diminished TCR signaling for IFN-γ and TNF production, their responses to PMA and Ionomycin are intact. Therefore, they may remain capable of producing low levels of effector molecules in response to environmental inflammatory factors that are constitutively observed in aged tissues [22, 27]. Alternatively, it is possible that enhanced accumulation of those “functionally-intact” T RM cells such as D b -PA T RM cells may be responsible for the persistent tissue inflammation and fibrosis in aged hosts.…”

Two waves of pro-inflammatory factors are released during the influenza A virus (IAV)-driven pulmonary immunopathogenesis

“…Though these infiltrated cells are required for host protection and recovery, they can also exacerbate the immune injury to the lung and worsen clinical symptoms. The activation of neutrophils was recently reported associated with the most severe and acute infection of IAV in patients [7], and old mice infected with IAV would induced excessive levels of neutrophils and higher levels of cytokines [8], indicating that neutrophils have important roles in the IAV-driven immunopathogenesis Because of the double-edged sword role played by these infiltrated immune cells and the cytokines/chemokines they produced, it is necessary to further explore immune reaction profiles of the lung at different time points during IAV infection.…”