AUTHOR=Hwang Seungyeon , Cho Jae-Min , Yoon Yeo-Jun , Seo Sunyoung , Hong Yongpyo , Lim Jae-Yol 

TITLE=Retroductal dexamethasone administration promotes the recovery from obstructive and inflammatory salivary gland dysfunction

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1418703

DOI=10.3389/fimmu.2024.1418703

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Salivary gland dysfunction, often resulting from salivary gland obstruction-induced inflammation, is a prevalent condition. Corticosteroid, known for its anti-inflammatory and immunomodulatory properties, is commonly prescribed in clinics. This study investigates the therapeutic implications and potential side effects of dexamethasone on obstructive sialadenitis recovery using duct ligation mice and salivary gland organoid models.</p></sec><sec><title>Methods</title><p>Functional and pathological changes were assessed after administering dexamethasone to the duct following deligation 2 weeks after maintaining ligation of the mouse submandibular duct. Additionally, lipopolysaccharide- and tumor necrosis factor-induced salivary gland organoid inflammation models were established to investigate the effects and underlying mechanisms of action of dexamethasone.</p></sec><sec><title>Results</title><p>Dexamethasone administration facilitated SG function restoration, by increasing salivary gland weight and saliva volume while reducing saliva lag time. Histological evaluation revealed, reduced acinar cell atrophy and fibrosis with dexamethasone treatment. Additionally, dexamethasone suppressed pro-inflammatory cytokines IL-1β and TNF expression. In a model of inflammation in salivary gland organoids induced by inflammatory substances, dexamethasone restored acinar markers such as <italic>AQP5</italic> gene expression levels, while inhibiting pro-inflammatory cytokines <italic>TNF</italic> and <italic>IL6</italic>, as well as chemokines <italic>CCL2</italic>, <italic>CXCL5</italic>, and <italic>CXCL12</italic> induction. Macrophages cultured in inflammatory substance-treated media from salivary gland organoid cultures exhibited pro-inflammatory polarization. However, treatment with dexamethasone shifted them towards an anti-inflammatory phenotype by reducing M1 markers (<italic>Tnf</italic>, <italic>Il6</italic>, <italic>Il1b</italic>, and <italic>Cd86</italic>) and elevating M2 markers (<italic>Ym1</italic>, <italic>Il10</italic>, <italic>Cd163</italic>, and <italic>Klf4</italic>). However, high-dose or prolonged dexamethasone treatment induced acino-ductal metaplasia and had side effects in both <italic>in vivo</italic> and <italic>in vitro</italic> models.</p></sec><sec><title>Conclusions</title><p>Our findings suggest the effectiveness of corticosteroids in treating obstructive sialadenitis-induced salivary gland dysfunction by regulating pro-inflammatory cytokines.</p></sec>