Possible link between cystic fibrosis specific lipid A adaptations by Pseudomonas aeruginosa and disease associated hyperinflammation.

Abstract

Abstract Pseudomonas aeruginosa infection in cystic fibrosis (CF) lung disease causes airway neutrophilia and hyperinflammation without being cleared effectively. We evaluated the immunostimulatory activities of lipid A variants synthesized by P. aeruginosa (PA) exclusively in CF patients to determine if they correlate with CF disease severity and progression. One third of the PA isolates from CF patients with late severe stage express a unique hepta–acylated lipid A; hepta-1855 (m/z=1855) isoform. In primary cell cultures, we found that hepta-1855 functioned as a potent TLR4 agonist by priming neutrophil respiratory burst and stimulating strong chemokine response (interleukin-8 or IL-8) from monocytes and neutrophils. Hepta-1855 also had a potent survival effect on neutrophils. However, it was less efficient in inducing neutrophil granule exocytosis and was also less potent in triggering pro-inflammatory TNF-α response from monocytes. A precursor hexa-1616, found in hepta-1855 containing LPS mixtures, did not have direct inflammatory activity on neutrophils but induced moderate IL-8 response. Together, our data suggest a potential contribution of hepta-1855 to late CF stage associated excessive inflammatory burden by recruiting neutrophils via IL-8 and promoting their maintenance through its survival effect. Being a chemoattractant stimulus, hexa-1616, may serve as an accomplice to hepta-1855. Moreover, the relative inefficiency of hepta-1855 in triggering degranulation may partly explain the persistence of PA in CF disease in spite of neutrophil dominated inflammation.