Acidosis Potentiates the Host Proinflammatory Interleukin-1β Response to Pseudomonas aeruginosa Infection

Abstract

Infection by Pseudomonas aeruginosa, and bacteria in general, frequently promotes acidification of the local microenvironment, and this is reinforced by pulmonary exertion and exacerbation. However, the consequence of an acidic environment on the host inflammatory response to P. aeruginosa infection is poorly understood. Here we report that the pivotal cellular and host proinflammatory interleukin-1␤ (IL-1␤) response, which enables host clearance of the infection but can produce collateral inflammatory damage, is increased in response to P. aeruginosa infection within an acidic environment. Synergistic mechanisms that promote increased IL-1␤ release in response to P. aeruginosa infection in an acidic environment are increased pro-IL-1␤ induction and increased caspase-1 activity, the latter being dependent upon a functional type III secretion system of the bacteria and the NLRC4 inflammasome of the host. Using an in vivo peritonitis model, we have validated that the IL-1␤ inflammatory response is increased in mice in response to P. aeruginosa infection within an acidic microenvironment. These data reveal novel insights into the regulation and exacerbation of inflammatory responses to P. aeruginosa.

Acidosis increases the susceptibility of respiratory epithelial cells toPseudomonas aeruginosa-induced cytotoxicity

“…Before the cells were used in experiments, growth medium was removed, and preequilibrated pH medium at pH 6.7 or 7.3 was added to the wells. The pH medium consists of HBSS buffered with 25 mM HEPES to the desired pH and, where indicated, 1% FBS and is described elsewhere (58).…”

“…The PA103 exoUT ϩ pUCP-exoU-S142A strain was provided by D. Frank (Medical College of Wisconsin, Milwaukee, WI); all other PA103 strains were provided by B. Kazmierczak (Yale University, New Haven, CT). All strains have been previously used and published (21,47,48,51,58). Bacteria were cultured overnight at 37°C and subsequently subcultured for 2 h in LB.…”

“…Acidosis at these sites, with pH values below the physiological norm of 7.4, is thought to contribute to pathology and pathogenesis. Previous studies have demonstrated that low pH affects a variety of host responses, including regulation of the transcription factor NF-B, neutrophil activation, and production of proinflammatory cytokines (7,16,30,33,37,42,44,55,57,58), that can play an important role in the clearance of a P. aeruginosa infection. Furthermore, acidic pH impairs the bactericidal activity of antimicrobial peptides, which at neutral pH are capable of rapidly killing P. aeruginosa (1,40).…”

Bacterial secretion systems and regulation of inflammasome activation

“…Pseudomonas-triggered inflammasome activation induces autophagy, which seems to be associated with defective killing of the bacteria. Moreover, in an acidic microenvironment, as is typically the case in bacterial infection foci, Pseudomonas T3SS triggers enhanced inflammasome activation of immune cells [195]. This may be significant, as acidic conditions are known to favor autophagy [196][197][198], further assisting bacterial survival.…”

New advances in invasive aspergillosis immunobiology leading the way towards personalized therapeutic approaches

“…A. fumigatus is known to activate NLRP3- (Karki et al, 2015; Moretti et al, 2014; Said-Sadier et al, 2010) and AIM2- (Karki et al, 2015) containing inflammasomes in order to mature and secrete IL-1β. Hypoxia reduces the local pH within the pulmonary tract, which is also known to modulate the activity of the NLRP3 inflammasome and IL-1β release (Torres et al, 2014). …”