Metabolic Adaptation of Neutrophils in Cystic Fibrosis Airways Involves Distinct Shifts in Nutrient Transporter Expression

Abstract

Inflammatory conditions can profoundly alter human neutrophils, a leukocyte subset generally viewed as terminally differentiated and catabolic. In cystic fibrosis (CF) patients, neutrophils recruited to CF airways show active exocytosis and sustained phosphorylation of prosurvival, metabolic pathways. Because the CF airway lumen is also characterized by high levels of free glucose and amino acids, we compared surface expression of Glut1 (glucose) and ASCT2 (neutral amino acids) transporters, as well as that of PiT1 and PiT2 (inorganic phosphate transporters), in blood and airway neutrophils, using specific retroviral envelope-derived ligands. Neither nutrient transporter expression nor glucose uptake was altered on blood neutrophils from CF patients compared with healthy controls. Notably, however, airway neutrophils of CF patients had higher levels of PiT1 and Glut1 and increased glucose uptake compared with their blood counterparts. Based on primary granule exocytosis and scatter profiles, CF airway neutrophils could be divided into two subsets, with one of the subsets characterized by more salient increases in Glut1, ASCT2, PiT1, and PiT2 expression. Moreover, in vitro exocytosis assays of blood neutrophils suggest that surface nutrient transporter expression is not directly associated with primary (or secondary) granule exocytosis. Although expression of nutrient transporters on CF blood or airway neutrophils was not altered by genotype, age, gender, or Pseudomonas aeruginosa infection, oral steroid treatment decreased Glut1 and PiT2 levels in blood neutrophils. Thus, neutrophils recruited from blood into the CF airway lumen display augmented cell surface nutrient transporter expression and glucose uptake, consistent with metabolic adaptation.

CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease

“…However, the relevance of these murine findings to human conditions, particularly cystic fibrosis lung disease, remains to be established. Based on our previous experience [19] and this present study we have no evidence that CXCR4-expressing granulocytes in cystic fibrosis airways simply represent apoptotic or necrotic cells, but rather suggest that this granulocyte phenotype reflects microenvironmental adaption and cellular reprogramming, as proposed previously [20,21,35].…”

Neutrophils in cystic fibrosis

“…Therefore, additional studies described that neutrophils migrating into CF airways can adapt to this enriched milieu by positively modulating their G-CSF receptor (CD114) (Makam et al, 2009) and their metabolite transporters, notably for glucose (GLUT1 or SLC2A1) and inorganic phosphate (PiT1 or SLC20A1) when compared to blood neutrophils. Interestingly, by looking directly into airway subsets, CF airway neutrophils displayed further regulation profile in PiT2 (or SLC20A2, another inorganic phosphate transporter) as well as in amino acid transporter (ASCT2 or SLC1A5), involved in the supplementation of essential amino acids regulating mTOR (Nicklin et al, 2009;Laval et al, 2013). Taken together, up-regulation of the anabolic prosurvival mTOR pathway and changes in surface receptors suggest that neutrophils homing to CF lungs undergo a concerted set of reprogramming processes.…”

“…Given the emerging concept of neutrophil heterogeneity and plasticity (Makam et al, 2009;Laval et al, 2013;Kruger et al, 2015), neutrophil phenotype-specific targeting approaches could be reasonable, but require further preclinical and clinical studies.…”

Polymorphonuclear Leukocytes Restrict Growth of Pseudomonas aeruginosa in the Lungs of Cystic Fibrosis Patients

“…Denitrification during chronic lung infection in CF may also be used by other CF pathogens because we recently demonstrated the genetic setup for denitrification as well as anaerobic N 2 O production in Achromobacter xylosoxidans (43), an emerging CF pathogen that induces an inflammatory response resembling the response induced by P. aeruginosa (44). Consumption of glucose by activated PMNs (45,46) may lead to a reduction in available glucose, which may also limit the growth of P. aeruginosa (47,48). However, the high levels of glucose (2 to 4 mM) in CF airway fluids (49) suggest that bacterial growth in infected mucus is not limited by available glucose.…”