Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease

Nature Medicine. 2007. 13, 1423-1430

Speaker: 李明翰                   Time: 14:10~15:00, Feb. 27, 2008

Commentator: 謝奇璋 醫師         Place: Room 601

Abstract:

Neutrophils play an important role in innate defense system against bacterial infections. Stimulation of neutrophils with IL-8 can promote phospholipase D activation and respiratory burst through chemokine receptor CXCR1.¹ Clinical studies indicate that individuals with chronic lung disease such as cystic fibrosis and chronic obstructive pulmonary disease (COPD) show high levels of IL-8 and neutrophils in airway fluids.² Nevertheless, these patients are usually colonized by bacterial pathogens such as Pseudomonas aeruginosa in the lung.² In this study, the authors investigated the association of insufficient bacterial clearance with impairment of CXCR1 in chronic lung diseases. They found that IL-8 enhanced bacterial killing by neutrophils through CXCR1 but not CXCR2. They also observed that neutrophils from airway fluids of patients with chronic lung diseases lost surface CXCR1 expression and bacterial killing capacity. The decreased expression of CXCR1 was due to the cleavage process by airway protease. The cleaved CXCR1 fragments were glycosylated and stimulated IL-8 production in bronchial epithelial cells through Toll-like receptor 2 signaling. In addition, the authors used a1-antitrypsin to inhibit protease activity and restore CXCR1 expression on neutrophils. Treatment with a1-antitrypsin improved bacterial killing capacity in patients with cystic fibrosis. Thus, the cleavage of CXCR1 on neutrophils and subsequent identification of the biological function of the soluble CXCR1 fragments demonstrated a new pathophysiological mechanism of chronic lung diseases.

References:

1.   Jones, S.A., Wolf, M., Qin, S., Mackay, C.R. & Baggiolini, M. Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. Proc Natl Acad Sci U S A 93, 6682-6686 (1996).

2.   Stockley, R.A. Neutrophils and the pathogenesis of COPD. Chest 121, 151S-155S (2002).