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Review
. 2022 Apr 28;139(17):2622-2631.
doi: 10.1182/blood.2021014699.

Neutrophil dysfunction in the pathogenesis of cystic fibrosis

Guoshun Wang  1   2 , William M Nauseef  3   4
Affiliations
Review

Neutrophil dysfunction in the pathogenesis of cystic fibrosis

Guoshun Wang et al. Blood. .

Abstract

Polymorphonuclear neutrophils (PMNs) figure prominently in host defense against infection and in noninfectious inflammation. Mobilized early in an inflammatory response, PMNs mediate immediate cellular defense against microbes and orchestrate events that culminate in cessation of inflammation and restoration of homeostasis. Failure to terminate the inflammatory response and its causes can fuel exuberant inflammation characteristic of many human diseases, including cystic fibrosis (CF), an autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator. CF affects multiple end organs, with persistent bacterial infection and chronic neutrophilic inflammation in airways predominating the clinical picture. To match the diverse microbial challenges that they may encounter, PMNs possess a variety of antimicrobial systems to slow or kill invading microorganisms confined in their phagosomes. Prominent among PMN defense systems is their ability to generate hypochlorous acid, a potent microbicide, by reacting oxidants generated by the NADPH oxidase with myeloperoxidase (MPO) released from azurophilic granules in the presence of chloride (Cl-). Products of the MPO-H2O2-Cl system oxidize susceptible biomolecules and support robust antimicrobial action against many, but not all, potential human pathogens. Underscoring that the MPO-H2O2-Cl system is integral to optimal host defense and proper regulation of inflammation, individuals with defects in any component of this system, as seen in chronic granulomatous disease or MPO deficiency, incur increased rates or severity of infection and signs of dysregulated inflammatory responses. We focus attention in this review on the molecular basis for and the clinical consequences of defects in the MPO-H2O2-Cl system because of the compromised Cl transport seen in CF. We will discuss first how the MPO-H2O2-Cl system in healthy PMNs participates in host defense and resolution of inflammation and then review how a defective MPO-H2O2-Cl system contributes to the increased susceptibility to infection and dysregulated inflammation associated with the clinical manifestations of CF.

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Figures

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Graphical abstract
Figure 1.
Figure 1.
Chloride is the predominant anion that regulates phagosomal oxidant production in PMN phagosomes. NADPH oxidase transfers electrons into the phagosomal lumen, thereby creating a transmembrane potential that activates voltage-gated proton channels, such as Hv1, to conduct an influx of protons. In addition, the ATP-driven proton pump vacuolar-type ATPase (V-ATPase) actively pumps protons in the same direction. Other cations such as K+, Na+, and Ca2+ can be transported into phagosomes via monovalent or divalent cation/H+ exchangers, or K+/Cl‒ symporter. To counterbalance the influx of the cations, Cl‒ is transported through chloride channels, including CFTR, CaCC, and voltage-gated ClCs.
Figure 2.
Figure 2.
Killing of PsA by normal PMNs is chloride dependent. Normal human peripheral blood PMNs were allowed to ingest serum-opsonized PsA (20:1 PsA:PMN) in sodium gluconate chloride-free Ringer’s buffer containing 10% dialyzed human AB serum for 20 minutes at 37°C. The uningested PsAs were removed by low-speed centrifugation, and the cell pellets containing PMNs harboring PsA resuspended in Ringer’s buffer containing varied concentrations of chloride (0-127 mM) and 10% dialyzed serum. After the zero time point was sampled to determine the initial number of viable PsAs, PsA-laden PMNs were incubated with shaking at 37°C, and aliquots were taken at the indicated time points (10, 20, 30, and 40 minutes). The fraction of viable PsAs relative to those at zero time point was determined. The data are plotted on a semi-log scale relative to the viable bacteria present at zero time. [Cl], chloride concentration; K, killing rate constant.
Figure 3.
Figure 3.
Lack of chloride influx in phagosomes of CF PMNs. Serum-opsonized zymosan particles covalently conjugated with a chloride probe (MQHA, 6-methoxyquinoline-N-6-hexanoic acid) and reference probe (TMR, tetramethylrhodamine) were ingested by normal or CF PMNs. Intraphagosomal chloride levels were continuously measured by quantitative fluorescence microscopy. The probe-laden cells were bathed in different chloride buffers in the following order: (1) sodium gluconate chloride-free Ringer’s buffer (NaGlu R), (2) sodium chloride (135 mM) Ringer’s buffer (NaCl R), and (3) chloride-free Ringer’s buffer (NaGlu R). The phagosomal chloride concentration of normal PMNs (○) rapidly respond to the change in extracellular chloride change, whereas that of CF PMN (●) had no response. At 30 minutes, a series of isoosmotic 0.1% Triton X-100 solutions containing varied chloride concentrations (0-135 mM) was introduced sequentially to calibrate the system at 6-minute intervals. Reprinted from reference .
Figure 4.
Figure 4.
CF neutrophil killing of P. aeruginosa is impaired and further compromised in a chloride-poor environment. The rate of PsA killing, indicated by the first-order rate constant (% per minute), by normal (solid bars) or CF (open bars) PMNs in chloride-poor medium (0 mM chloride) or chloride-rich medium (127 mM chloride). Error bars represent standard error of the mean (n = 5 donors each). **P ≤ .05, for comparisons of the indicated means by Student t test. Reprinted from reference .
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