Regulation of nuclear factor-κB in autoimmunity

Abstract

Nuclear factor (NF)-κB transcription factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF-κB signaling contribute to the pathogenesis of immunological disorders. NF-κB is a well-known proinflammatory mediator, and its deregulated activation is associated with the chronic inflammation of autoimmune diseases. Paradoxically, NF-κB plays a crucial role in the establishment of immune tolerance, including both central tolerance and the peripheral function of regulatory T (Treg) cells. Thus, defective or deregulated activation of NF-κB may contribute to autoimmunity and inflammation, highlighting the importance of tightly controlled NF-κB signaling. This review focuses on recent progress regarding NF-κB regulation and its association with autoimmunity.

Fig. 1. Paradoxical roles of NF-κB in the regulation of autoimmunity and inflammation

NF-κB is involved in both the stimulation (Yang) and repression (Yin) of autoimmunity and inflammation. NF-κB promotes autoimmunity and inflammation by mediating the activation and differentiation of autoimmune and inflammatory T cells, such as Th17 cells. This is achieved either directly through a T cell-intrinsic function or indirectly via promoting the maturation and proinflammatory cytokine production of DCs. NF-κB suppresses autoimmunity and inflammation through mediating the development and immunosuppressive function of Treg cells. Canonical NF-κB pathway directly mediates this function, whereas noncanonical NF-κB pathway functions indirectly through mediating mTEC maturation, which is also crucial for central tolerance.

Fig. 2. A model of Treg cell regulation by the Ubc13-IKK signaling axis

Constant stimulation of the TCR by self-antigens may lead to chronic NF-κB activation via the Ubc13-IKK signaling axis, which in turn promotes the expression of SOCS1, IL-10, and possibly additional factors involved in the function and stability of Treg cells. The NF-κB-mediated SOCS1 induction also requires the synergy from STAT proteins, and the induced SOCS1 in turn restrains the signaling from receptors of IL-6 and IFNγ. Ablation of Ubc13, or IKKβ, disrupts the activation of NF-κB and attenuates the expression SOCS1 and IL-10. The reduced SOCS1 expression may cause heightened IL-6 and IFNγ signaling and induction of IFNγ and IL-17, thereby promoting autoimmunity and inflammation. The impaired expression of IL-10 and possibly other factors may also compromise the in vivo suppressive function of Treg cells.

Fig. 3. Negative regulation of BAFF-stimulated noncanonical NF-κB signaling by TBK1

BAFF stimulates both TACI and BAFFR, which mediate the canonical and noncanoncal NF-κB pathways, respectively. TACI, and to a lesser extent BAFFR, activates TBK1, which in turn negatively regulates noncanonical NF-κB signaling by promoting NIK degradation.