The resident pathobiont Staphylococcus xylosus in Nfkbiz-deficient skin accelerates spontaneous skin inflammation

Abstract

IκBζ, which is encoded by the Nfkbiz gene, is a member of the nuclear IκB family of proteins that act as transcriptional regulators via association with NF-κB. Nfkbiz-deficient (Nfkbiz −/−) mice develop spontaneous dermatitis; however, the underlying mechanism has yet to be elucidated. In our study, we found higher skin pathology scores and more serum IgE antibodies and trans-epidermal water loss in Nfkbiz −/− than in Nfkbiz-sufficient (Nfkbiz +/−) mice. There was also greater expansion of IFN-γ-, IL-17A-, and IL-22-secreting CD4+ T cells and of IL-17A-secreting γδ+ T cells in the skin of Nfkbiz −/− mice than in with Nfkbiz +/− mice. Pyrosequencing analysis showed decreased diversity of resident bacteria and markedly expanded Staphylococcus (S.) xylosus in the skin of Nfkbiz −/− mice. Oral administration of antibiotics including cephalexin and enrofloxacin ameliorated skin inflammation. Topical application of S. xylosus also resulted in the expansion of IL-17A-secreting CD4+ T cells along with high levels of pro-inflammatory cytokines and chemokines in the skin of Nfkbiz −/− mice. The expansion of commensal S. xylosus may be one cause of skin dysbiosis in Nfkbiz −/− mice and suggests that the Nfkbiz gene may play a regulatory role in the microbiota-skin immunity axis.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

“…This was possibly due to an increased expression of Il7 and Il15 in the skin of untreated K14-KO mice (Supplemental Figure 2D), which are both cytokines known to regulate tissue homeostasis of γδ T cells (21,22). These findings agree with a previous report detecting an expansion of T cells in the skin of global Nfkbiz-deficient mice because of a changed microbiome (23). Thus, we suggest that the elevated numbers of IL-17A-expressing γδ T cells in keratinocyte-specific IκBζ KO mice are independent of IMQ treatment and possibly due to a changed microbiome.…”

“…Similar to Ccl2, expression levels of Il1b and Il23a, which are required for Il17a induction in γδ T cells, were upregulated in untreated K14-KO mice. A previous report detected a similar expansion of T cells in the skin of global IκBζ-KO mice, which was attributed to alterations of the skin microbiome (23). Therefore, keratinocyte-derived IκBζ might not only be important for skin inflammation but also represent a critical regulator of the microbiome, thus explaining why IL-17A-producing γδ T cells expand in the skin of untreated K14-KO animals.…”

Association of a dysbiotic oral microbiota with the development of focal lymphocytic sialadenitis in IκB-ζ-deficient mice

“…IκB-ζ is induced by various microbial products, and subsequent regulation of the transcriptional activity of NF-κB may play a role in the maintenance of a homeostatic balance between the host and microbiome 14 . Indeed, dysbiosis of the skin microbiome in Nfkbiz −/− mice has been reported previously in association with dermatitis 15 . This study aimed to characterize the salivary gland phenotype of IκB-ζ-deficient mice and to investigate its association with the oral microbiota.…”

Integration of machine learning and meta-analysis identifies the transcriptomic bio-signature of mastitis disease in cattle

“…The critical role of IκBζ signaling in the regulation of immune responses has been revealed previously [ 78 , 79 ]. Like other IκB proteins, IκBζ has inhibitory effects on the transcription of inflammatory genes regulated by NF-κB such as tumor necrosis factor (TNF)-α, interleukin-1 (IL-1) [ 77 , 80 ] and IL-17A production from CD4+ T cells [ 81 ]. Furthermore, it has been demonstrated that IκBζ is indispensable for the expression of a subset of genes activated in TLR/IL-1R signaling pathways [ 77 ].…”