Document Type

Article

Publication Date

Winter 1-22-2013

Abstract

Background

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.

Methods and Principal Findings

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.

Conclusions

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.

Comments

Published: PLoS ONE 8(1): e54124. doi:http://dx.doi.org/10.1371/journal.pone.0054124

Funding: This work was supported by National Institutes of Health grant GM066882 and a research contract from Boehringer Ingelheim Pharmaceuticals, Inc. both awarded to KBM. NCI training grant 5 T32 CA009176 awarded to SS through the Genetics Graduate Program of Stony Brook University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Funding (in the form of a research contract from Boehringer Ingeliehim Pharmaceuticals, Inc. awarded to the Research Foundation of Stony Brook for KBM’s research) initially partially supported the generation of the conditional knockout mice used in this work. However, these mice were primarily generated for a separate study published in collaboration with the authors’ colleagues at Boehringer Ingelheim Pharmaceuticals, Inc. (see Penzo, M., et al. 2010). The authors’ contract with Boehringer Ingelheim Pharmaceuticals, Inc. expired in 2010 and they no longer participate in their research involving these IKK conditional mice. Thus the authors are free to use these mice in any new research projects that they may design and, importantly, provide them to scientific colleagues at their own discretion with no obligation or ties whatsoever to Boehringer Ingelheim Pharmaceuticals, Inc. Neither KBM nor SS have ever been paid as Boehringer consultants. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

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