Enhanced Apoptosis by Disruption of the STAT3-IκB-ζ Signaling Pathway in Epithelial Cells Induces Sjögren’s Syndrome-like Autoimmune Disease

Abstract

Sjögren's syndrome (SS) is an autoimmune disease characterized by exocrinopathy that leads to dry eye and mouth. Although lymphocyte infiltration into exocrine glands and the generation of autoantibodies have been reported in SS, its pathogenic mechanism remains elusive. Here, we show that mice lacking the transcriptional regulator IκB-ζ developed SS-like inflammation characterized by lymphocyte-infiltrated dacryoadenitis and SS-associated autoantibodies. In particular, epithelial cells, but not hematopoietic cells, lacking IκB-ζ were essential for the development of inflammation. IκB-ζ-deficient epithelial cells in the lacrimal glands exhibited enhanced apoptosis even in the absence of lymphocytes. Administration of caspase inhibitors ameliorated the inflammation, indicating the critical role of caspase-mediated apoptosis. Furthermore, epithelial cell-specific STAT3-deficient mice developed SS-like inflammation with impaired IκB-ζ expression in the lacrimal glands. Thus, this study reveals a pathogenic mechanism of SS in which dysfunction of epithelial cells caused by disruption of STAT3-mediated IκB-ζ induction elicits the activation of self-reactive lymphocytes.

<b>The role of IFN-γ in regulating Nfkbiz expression in epidermal </b><b>keratinocytes </b>

“…Our findings that both JAK/STAT and NF-κB pathways are important for the synergism are consistent with a previous report on CXCL10 (3). Although STAT3 is known to play a very important role in inducing Nfkbiz expression in immune cells among the STAT family (9,11,12), the central STAT molecule acting downstream of IFN-γ signaling is STAT1 or STAT2 rather than STAT3 (1,15). The precise role of STATs in the regulation of Nfkbiz expression seems to be complicated and further analysis is needed.…”

The Atypical Inhibitor of NF-κB, IκBζ, Controls Macrophage Interleukin-10 Expression

“…by its requirement for Th17 differentiation and expression of particular pro-inflammatory cytokines. Nevertheless, Nfkbiz Ϫ/Ϫ mice show a pro-inflammatory phenotype and M1 hyperpolarization of macrophages (15,16,24,25), suggesting that so far unknown anti-inflammatory mediators might be controlled by IB. In this study, we found that induction of the potent anti-inflammatory cytokine IL-10 by LPS but also by TLR2 agonists (data not shown) was strictly dependent on IB and strongly reduced in Nfkbiz Ϫ/Ϫ mice.…”

“…Furthermore, several other proinflammatory gene products, including IL-6, IL12p40, IL-17, IFN␥, and GM-CSF, have been found to be regulated by IB (16, 19 -23). Intriguingly, however, despite impaired expression of these pro-inflammatory cytokines, Nfkbiz Ϫ/Ϫ mice display a pro-inflammatory phenotype characterized by periocular inflammation, inflammatory skin alterations, and an M1 hyperpolarized macrophage state (15,16,24,25). In view of the phenotype of Nfkbiz Ϫ/Ϫ mice, we therefore investigated a potential role of IB for the regulation of IL-10 as an essential anti-inflammatory cytokine.…”

ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands

“…Furthermore, enhanced apoptosis has been related to the impairment of secretory function and generation of autoantigens (17). More recently, it was shown that administration of caspase inhibitors in mouse models of SS ameliorated inflammation, indicating a critical role for caspase-mediated apoptosis (32). The decrease in TNF-␣-mediated caspase-3 activation observed here suggests that AT-RvD1 blocks molecules upstream of caspase-3 (e.g., caspase-8 or TNF receptor type 1; Fig.…”