Faculty Collaboration Database

Dysregulated Calcium Homeostasis in Cystic Fibrosis Neutrophils Leads to Deficient Antimicrobial Responses. J Immunol 2018 Oct 01;201(7):2016-2027

Date

08/19/2018

Pubmed ID

30120123

Pubmed Central ID

PMC6143431

DOI

10.4049/jimmunol.1800076

Scopus ID

2-s2.0-85053469523 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

Cystic fibrosis (CF), one of the most common human genetic diseases worldwide, is caused by a defect in the CF transmembrane conductance regulator (CFTR). Patients with CF are highly susceptible to infections caused by opportunistic pathogens (including Burkholderia cenocepacia), which induce excessive lung inflammation and lead to the eventual loss of pulmonary function. Abundant neutrophil recruitment into the lung is a key characteristic of bacterial infections in CF patients. In response to infection, inflammatory neutrophils release reactive oxygen species and toxic proteins, leading to aggravated lung tissue damage in patients with CF. The present study shows a defect in reactive oxygen species production by mouse Cftr^-/- , human F508del-CFTR, and CF neutrophils; this results in reduced antimicrobial activity against B. cenocepacia Furthermore, dysregulated Ca²⁺ homeostasis led to increased intracellular concentrations of Ca²⁺ that correlated with significantly diminished NADPH oxidase response and impaired secretion of neutrophil extracellular traps in human CF neutrophils. Functionally deficient human CF neutrophils recovered their antimicrobial killing capacity following treatment with pharmacological inhibitors of Ca²⁺ channels and CFTR channel potentiators. Our findings suggest that regulation of neutrophil Ca²⁺ homeostasis (via CFTR potentiation or by the regulation of Ca²⁺ channels) can be used as a new therapeutic approach for reestablishing immune function in patients with CF.

Author List

Robledo-Avila FH, Ruiz-Rosado JD, Brockman KL, Kopp BT, Amer AO, McCoy K, Bakaletz LO, Partida-Sanchez S

Author

Kenneth Brockman PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Animals
Burkholderia Infections
Burkholderia cenocepacia
Calcium
Calcium Channels
Calcium Signaling
Child
Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
Female
Homeostasis
Humans
Immunity
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
NADPH Oxidases
Neutrophil Infiltration
Neutrophils
Pneumonia
Reactive Oxygen Species