Graduate Program in Genetics, Stony Brook University, Stony Brook, New York, USA.
PLoS One. 2013;8(1):e54124. doi: 10.1371/journal.pone.0054124. Epub 2013 Jan 22.
The NF-κB activating kinases, IKKα and IKKβ, are key regulators of inflammation and immunity in response to infection by a variety of pathogens. Both IKKα and IKKβ have been reported to modulate either pro- or anti- inflammatory programs, which may be specific to the infectious organism or the target tissue. Here, we analyzed the requirements for the IKKs in myeloid cells in vivo in response to Francisella tularensis Live Vaccine Strain (Ft. LVS) infection.
In contrast to prior reports in which conditional deletion of IKKβ in the myeloid lineage promoted survival and conferred resistance to an in vivo group B streptococcus infection, we show that mice with a comparable conditional deletion (IKKβ cKO) succumb more rapidly to lethal Ft. LVS infection and are unable to control bacterial growth at sublethal doses. Flow cytometry analysis of hepatic non-parenchymal cells from infected mice reveals that IKKβ inhibits M1 classical macrophage activation two days post infection, which has the collateral effect of suppressing IFN-γ(+) CD8(+) T cells. Despite this early enhanced inflammation, IKKβ cKO mice are unable to control infection; and this coincides with a shift toward M2a polarized macrophages. In comparison, we find that myeloid IKKα is dispensable for survival and bacterial control. However, both IKKα and IKKβ have effects on hepatic granuloma development. IKKα cKO mice develop fewer, but well-contained granulomas that accumulate excess necrotic cells after 9 days of infection; while IKKβ cKO mice develop numerous micro-granulomas that are less well contained.
Taken together our findings reveal that unlike IKKα, IKKβ has multiple, contrasting roles in this bacterial infection model by acting in an anti-inflammatory capacity at early times towards sublethal Ft. LVS infection; but in spite of this, macrophage IKKβ is also a critical effector for host survival and efficient pathogen clearance.
NF-κB 激活激酶 IKKα 和 IKKβ 是各种病原体感染后炎症和免疫反应的关键调节因子。已有报道称 IKKα 和 IKKβ 均可调节促炎或抗炎程序，这可能特定于感染病原体或靶组织。在此，我们分析了 IKKs 在体内髓样细胞中对弗朗西斯氏菌活疫苗株（Ft. LVS）感染的反应中的需求。
与先前的报道相反，髓系中 IKKβ 的条件性缺失促进了生存并赋予了对体内 B 组链球菌感染的抗性，我们发现具有类似条件性缺失（IKKβ cKO）的小鼠对致死性 Ft. LVS 感染的反应更快，并且无法在亚致死剂量下控制细菌生长。对感染小鼠肝非实质细胞的流式细胞术分析表明，IKKβ 在感染后两天抑制 M1 经典巨噬细胞激活，这具有抑制 IFN-γ（+）CD8（+）T 细胞的附带作用。尽管有这种早期增强的炎症，IKKβ cKO 小鼠仍无法控制感染；这与 M2a 极化巨噬细胞的转变一致。相比之下，我们发现髓系 IKKα 对于生存和细菌控制是可有可无的。然而，IKKα 和 IKKβ 对肝肉芽肿的发展都有影响。IKKα cKO 小鼠形成的肉芽肿较少，但在感染 9 天后积累了过多的坏死细胞；而 IKKβ cKO 小鼠形成的肉芽肿较多，但包绕较差。
总的来说，我们的研究结果表明，与 IKKα 不同，IKKβ 在这个细菌感染模型中具有多种相反的作用，即在亚致死性 Ft. LVS 感染的早期通过抗炎作用发挥作用；但尽管如此，巨噬细胞 IKKβ 也是宿主生存和有效清除病原体的关键效应因子。
