With Friends Like These: The Complex Role of Neutrophils in the Progression of Severe Pneumonia

Abstract

Pneumonia is a leading cause of death from infection in the United States and across the globe. During pulmonary infection, clear resolution of host inflammatory responses occurs in the absence of appreciable lung damage. Neutrophils are the first wave of leukocytes to arrive in the lung upon infection. After activation, neutrophils traffic from the vasculature via transendothelial migration through the lung interstitium and into the alveolar space. Successful pulmonary immunity requires neutrophil-mediated killing of invading pathogens by phagocytosis and release of a myriad of antimicrobial molecules, followed by resolution of inflammation, neutrophil apoptosis, and clearing of dead or dying neutrophils by macrophages. In addition to their antimicrobial role, it is becoming clear that neutrophils are also important modulators of innate and adaptive immune responses, primarily through the release of cytokines and recruitment of additional waves of neutrophils into the airways. Though typically essential to combating severe pneumonia, neutrophil influx into the airways is a double-edged sword: Overzealous neutrophil activation can cause severe tissue damage as a result of the release of toxic agents including proteases, cationic polypeptides, cytokines, and reactive oxygen species (ROS) aimed at killing invading microbes. In extreme cases, the damage caused by neutrophils and other innate immune mediators become the primary source of morbidity and mortality. Here, we review the complex role of neutrophils during severe pneumonia by highlighting specific molecules and processes that contribute to pulmonary immunity, but can also drive progression of severe disease. Depending on the identity of the infectious agent, enhancing or suppressing neutrophil-mediated responses may be key to effectively treating severe and typically lethal pneumonia.

Keywords: neutrophils; pneumonia; pulmonary damage; pulmonary immunity; pulmonary infection.

Figure 1

Lung alveoli during infection. (A) Under steady state conditions, alveolar macrophages (orange) survey the alveolar space, and neutrophils are present in the pulmonary vasculature. (B) During infection, neutrophils (green) migrate into the alveolar space, where they can degranulate, facilitate an oxidative burst, and along with alveolar macrophages phagocytose and kill invading microbes. Antimicrobial peptides and enzymes are released during degranulation, but cause minimal tissue destruction that is ultimately repaired. (C) During severe pneumonia, as invading microbes persist neutrophils continue to flood the airways, potentially releasing a myriad of antimicrobial peptides, enzymes and ROS. As infection progresses this process continues to the detriment of the host, causing excessive tissue damage and disrupting the epithelial-capillary barrier, resulting in hemorrhage, edema, and compromise of pulmonary function.

Figure 2

Neutrophil Granules. Neutrophils are armed with an arsenal of tools for eliminating invading microbes, including four distinct granules containing a variety of antimicrobial peptides and enzymes, as well as an NADPH oxidase in the phagosomal membrane. Granule contents can be released at the cell surface via degranulation or into the phagolysozome containing a target microbe. Secretory vesicles are the first to be released and primarily contain membrane proteins to facilitate adherence during migration, followed by tertiary granules, and finally primary and secondary granules at the site of inflammation.