Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways.
Blood neutrophils recruited to cystic fibrosis (CF) airways are believed to be rapidly killed by resident bacteria and to passively release elastase and other toxic by-products that promote disease progression. By single-cell analysis, we demonstrate that profound functional and signaling changes readily occur within viable neutrophils recruited to CF airways, compared with their blood counterparts. Airway neutrophils have undergone conventional activation, as shown by decreased intracellular glutathione, increased lipid raft assembly, surface mobilization of CD11b+ and CD66b+ granules, and increased levels of the cytoskeleton-associated phospho-Syk kinase. Unexpectedly, they also mobilize to the surface CD63+ elastase-rich granules, usually confined intracellularly, and lose surface expression of CD16 and CD14, both key receptors in phagocytosis. Furthermore, they express CD80, major histocompatibility complex type II, and the prostaglandin D2 receptor CD294, all normally associated with other lineages, which reflects functional reprogramming. This notion is reinforced by their decreased total phosphotyrosine levels, mirroring a postactivated stage, and increased levels of the phospho-S6 ribosomal protein, a key anabolic switch. Thus, we identified a subset of neutrophils within CF airways with a viable but dysfunctional phenotype. This subset provides a possible therapeutic target and indicates a need to revisit current paradigms of CF airway disease.
Tirouvanziam
Rabindra
R
Departments of Pediatrics, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. tirouvan@stanford.edu
Gernez
Yael
Y
Conrad
Carol K
CK
Moss
Richard B
RB
Schrijver
Iris
I
Dunn
Colleen E
CE
Davies
Zoe A
ZA
Herzenberg
Leonore A
LA
Herzenberg
Leonard A
LA
D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers; D002465:Cell Movement; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology*; D010586:Phagocytes / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology; D015398:Signal Transduction
D015703:Antigens, CD; D015415:Biomarkers; D000939:Epitopes; D011971:Receptors, Immunologic