IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Abstract

IL-17–producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A–producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS−/− Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS−/− mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.

IL-17 Signaling: The Yin and the Yang

“…Despite its name, IκBζ acts primarily as a driver of transcription rather than an inhibitor. IL-17 induces both IκBζ mRNA and protein expression, and IκBζ in turn positively activates numerous IL-17 target genes in cooperation with NF-κB [69, 70, 73–75]. Additionally, IκBζ facilitates IL-17-induced gene expression by suppressing expression of miR-23b, an inhibitor of IL-17 signaling [76].…”

NF‐κB signaling in B‐1 cell development

“…IκBNS was originally reported as a repressor of inflammation because the absence of IκBNS was associated with prolonged production of inflammatory cytokines in macrophages . On the contrary, IκBNS was shown to be required for the development of B‐1 cells and regulatory T (T reg ) and T helper 17 (T H 17) cells, indicating a positive regulatory role of IκBNS for classical NF‐κB signaling in these cells . For an overview of atypical IκB proteins, see Ref.…”

A hypermorphic Nfkbid allele represents an Idd7 locus gene contributing to impaired thymic deletion of autoreactive diabetogenic CD8+ T-cells in NOD mice

“…6F). Previous reports indicated Nfkbid is a direct regulator of IL-10 (36). Proportions of FoxP3 + and FoxP3 − CD4 + T-cells producing immunosuppressive IL-10 upon ex vivo stimulation were significantly lower in Nfkbid deficient than intact NOD mice (Fig.…”

“…In order to perform total protein normalization, each sample was loaded in duplicates; one capillary was used for immunodetection of Nfkbid and the second for total protein quantification. A 1:100 dilution of rabbit polyclonal anti-Nfkbid (36) with a 60 min incubation time was used for immunodetection. Chemiluminescent signal was captured and the resulting image was analyzed by the Compass for Simple Western software package (ProteinSimple).…”