IKKβ in Myeloid Cells Controls the Host Response to Lethal and Sublethal Francisella tularensis LVS Infection

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.