Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

<jats:title>ABSTRACT</jats:title><jats:p>The bacterial pathogen<jats:named-content content-type="genus-species">Pseudomonas aeruginosa</jats:named-content>causes acute infections associated with significant morbidity and mortality.<jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content>elicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance.<jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content>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<jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content>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<jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content>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<jats:named-content content-type="genus-species">P. aeruginosa</jats:named-content>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.</jats:p>