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Infect Immun. 2014 Oct;82(10):4204-11. doi: 10.1128/IAI.02218-14. Epub 2014 Jul 28.

Distinct contributions of interleukin-1α (IL-1α) and IL-1β to innate immune recognition of Pseudomonas aeruginosa in the lung.

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Department of Medicine (Infectious Diseases), Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Medicine (Infectious Diseases), Yale University School of Medicine, New Haven, Connecticut, USA Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA


The bacterial pathogen Pseudomonas aeruginosa causes acute infections associated with significant morbidity and mortality. P. aeruginosa elicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance. P. aeruginosa lipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producing P. aeruginosa bacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1α was dispensable for neutrophil recruitment, while IL-1β was required. IL-1α secretion by macrophages infected with ExoU-producing P. aeruginosa isolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1α and IL-1β in the response to P. aeruginosa infection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.

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