Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection

Abstract

BackgroundAlveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.MethodsMice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.ResultsInfluenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.ConclusionsNeutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.

Macrophages and neutrophils: dynamic duo or partners in crime?

“…Antibody-mediated depletion of neutrophils specifically reduced the amount of influenza-induced IL-1β but not IL-6 or tumour necrosis factor-alpha, suggesting that the neutrophils were directly responsible for this increase in IL-1β 8. Moreover, neutrophil depletion only reduced viral-induced, not bacterial-induced, release of IL-1β.…”

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“…Furthermore, these increased neutrophil populations exhibited impaired antimicrobial activity compared to single-infected equivalents, and the increased presence of these cells appears to drive pathology to influenza. 26 Such observations suggest excessive neutrophil recruitment as a major factor in secondary bacterial mortality. A further study demonstrated that influenza infection appears to drive massive alveolar macrophage depletion (in some cases up to 90% depletion); after which secondary bacterial pneumonia occurs.…”