IL-1b-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKb

Michael, K. et al. Nature Immunology. 12:144-51 (2011)

Student: Tsan-Tzu Yang (楊璨滋)                                  Time: 15:00~16:00, Apr. 13, 2011

Commentator: Dr. Yee-Shin Lin (林以行 教授)          Place: Room 601

Abstract

Neutrophils are the first line of innate immune defense against infection and its diverse responses contribute to pathological or inflammatory processes. Activated neutrophil-mediated defense against microbes is mainly through phagocytosis and the release of soluble antimicrobi­als (1). After microbial clearance, neutrophils normally undergo apopto­sis (2), whereas the lack of apoptotic homeostasis may cause an increase number of neutrophils in circulating blood, so called neutrophilia. Transcription factor NF-κB and its activating kinase IKKβ play important role in molecular signaling of inflammatory activation. In this study, the authors found that neutrophilia and more neutrophil infiltration in bone marrow (BM), spleen, and liver after poly (I:C) injection in IKKb-deficient (Ikkb^D) mice than in wild type (WT) mice. Transplantation of Ikkb^D BM developedneutrophilia in WT mice and cell population expanded faster than WT cells. Furthermore, there was more IL-1b production in Ikkb^D mice than in WT mice after lipopolysaccharide challenge. Notably, deficiency of IL-1 receptor 1 in Ikkb^D mice (Ikkb^DIl1r1^-/-) maintained normal neutrophil counts. Treatment of IKKβ inhibitor ML120B also led to neutrophilia in WT mice, whereas combined-treatment of IL-1R antagonist anakinra reversed ML120B-induced neutrophilia. The results showed that hyperproliferating Ikkb^D BM cells made larger granulocyte-macrophage colony-forming units than others. Furthermore, WT neutrophils died faster than Ikkb^D and anti-apoptotic protein Bcl-x_L and its transcription factor STAT were upregulated, and cell cycle inhibi­tor p27 was downregulated in Ikkb^D neutrophils. Group A Streptococcus (GAS) was injected subcuta­neously into the mice and then observed development of necrotic skin lesions. The results showed that Ikkb^D mice had more neutrophilic infiltration in skin lesions accompanied by smaller lesions and survived longer than Ikkb^DIl1r1^-/- mice after GAS infection. Taken together, these results demonstrate that inhibition of IL-1b signaling prevent Ikkb^D-induced neutrophilia which is associated with hyperproliferation of granulocyte progenitors, prolonged proliferation of mature neutrophils, and alternative pathway to antibacterial activity.

References

1.      Nizet, V. et al. Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps. J. Mol. Med. 87:775-83 (2009).

2.      Bengtsson, T. et al. Activation of the granule pool of the NADPH oxidase accelerates apoptosis in human neutrophils. J. Leukoc. Biol. 65:196-204 (1999).