IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ

LC Hsu, T Enzler, J Seita, AM Timmer, CY Lee… - Nature …, 2011 - nature.com
LC Hsu, T Enzler, J Seita, AM Timmer, CY Lee, TY Lai, GY Yu, LC Lai, V Temkin, U Sinzig…
Nature immunology, 2011nature.com
Transcription factor NF-κB and its activating kinase IKKβ are associated with inflammation
and are believed to be critical for innate immunity. Despite the likelihood of immune
suppression, pharmacological blockade of IKKβ–NF-κB has been considered as a
therapeutic strategy. However, we found neutrophilia in mice with inducible deletion of IKKβ
(Ikkβ Δ mice). These mice had hyperproliferative granulocyte-macrophage progenitors and
pregranulocytes and a prolonged lifespan of mature neutrophils that correlated with the …
Abstract
Transcription factor NF-κB and its activating kinase IKKβ are associated with inflammation and are believed to be critical for innate immunity. Despite the likelihood of immune suppression, pharmacological blockade of IKKβ–NF-κB has been considered as a therapeutic strategy. However, we found neutrophilia in mice with inducible deletion of IKKβ (IkkβΔ mice). These mice had hyperproliferative granulocyte-macrophage progenitors and pregranulocytes and a prolonged lifespan of mature neutrophils that correlated with the induction of genes encoding prosurvival molecules. Deletion of interleukin 1 receptor 1 (IL-1R1) in IkkβΔ mice normalized blood cellularity and prevented neutrophil-driven inflammation. However, IkkβΔIl1r1−/− mice, unlike IkkβΔ mice, were highly susceptible to bacterial infection, which indicated that signaling via IKKβ–NF-κB or IL-1R1 can maintain antimicrobial defenses in each other's absence, whereas inactivation of both pathways severely compromises innate immunity.
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