Association of a dysbiotic oral microbiota with the development of focal lymphocytic sialadenitis in I\u03baB-\u03b6-deficient mice

Junho Lee,Eunji Choi,Ahreum Lee,Yeon Kyeong Ko,Jehan Alam,Youngnim Choi

doi:10.1038/s41522-020-00158-4

Abstract

Mice lacking IκB-ζ, a protein encoded by the Nfkbiz gene, spontaneously develop a Sjögren’s syndrome-like disease involving the lachrymal glands, but no salivary gland symptoms have been reported. We found that Nfkbiz−/− female mice presented a significantly reduced salivary flow rate, focal lymphocytic sialadenitis (FLS), and a dysbiotic oral microbiota at week 24. To dissect the contributions of genetic and environmental factors to the salivary gland phenotype, Nfkbiz+/+ and Nfkbiz−/− mice were cohoused after weaning and evaluated at week 20. Cohousing alleviated the salivary gland phenotype of Nfkbiz−/− mice but did not induce any disease phenotype in Nfkbiz+/+ mice. Additionally, the oral microbiota in the cohoused mice was synchronized toward that in Nfkbiz+/+ mice. In conclusion, IκB-ζ-deficient mice developed hyposalivation and FLS, in which a dysbiotic oral microbiota played an important role. This finding suggests that the dysbiotic oral microbiota could be a therapeutic target.

Highlights

Sjögren’s syndrome (SS) is a heterogeneous autoimmune disease characterized by dryness of the mouth and eyes[1]
Because an effect of gender on exocrine gland inflammation in mouse models of SS has been reported[17], only female mice were included in the study
A small degree of focal lymphocytic sialadenitis (FLS) was found in both genotypes

Summary

Introduction

Sjögren’s syndrome (SS) is a heterogeneous autoimmune disease characterized by dryness of the mouth and eyes[1]. Together with reduced saliva/tear secretion, lymphocytic infiltration of the salivary or lacrimal glands and the presence of autoantibodies, those against the SS antigen A/Ro, are important diagnostic criteria for SS2. The etiopathogenetic mechanisms of SS remain poorly understood, but it is believed that both genetic and environmental factors are involved in the development of the disease[3]. Among the several animal models for SS, mice lacking IκB-ζ, a protein encoded by the Nfkbiz gene, spontaneously develop an SS-like autoimmune disease from a single genetic defect. The phenotype of SS-like inflammation in Nfkbiz−/− mice includes lymphocyte-infiltrated dacryoadenitis, reduced tear secretion, and autoantibodies against the SS antigens A/Ro and B/La4. SS-like inflammation depends on IκB-ζ deficiency in epithelial cells but not IκB-ζ deficiency in lymphocytes[4]. IκB-ζ-deficient lachrymal gland epithelial cells present increased apoptosis[4], a phenomenon that is observed in the labial salivary glands of SS patients[6,7]

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Conclusion