Adamts18 Deficiency Causes Spontaneous SMG Fibrogenesis in Adult Mice
Adamts18 Deficiency Causes Spontaneous SMG Fibrogenesis in Adult Mice
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DOI：
10.1177/00220345211029270
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发表时间：
2021-07-29
影响因子：
7.6
通讯作者：
Zhang, W.
中科院分区：
文献类型：
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作者：
Yang, N.;Zhang, Q.;Zhang, W.
慢性硬化性颌下腺炎（也称为Kuttner瘤）的特征是伴随的颌下腺肿胀，继发于强烈的淋巴细胞浸润和纤维化。该病的发病机制尚不清楚，但与免疫紊乱有关。ADAMTS 18是细胞外蛋白酶ADAMTS超家族的成员。在这项研究中，我们发现Adamts 18在胚胎发育期间在小鼠的下颌下腺（SMG）中高度表达，并且在成年SMG组织中减少但保留。Adamts 18缺陷导致小鼠胚胎15.5天前胚胎SMG中裂缝形成和上皮分支减少。在Adamts 18（-/-）小鼠中未检测到分支后期或SMG形态学的显著组织学变化。然而，Adamts 18缺陷导致成年小鼠自发SMG纤维形成和纤维化。在8周龄时，Adamts 18（-/-）小鼠开始表现出SMG组织中轻度纤维化和CD 11b（+）细胞浸润的病理变化的最初迹象。在>= 8个月时，所有雄性和雌性Adamts 18（-/-）小鼠均出现单侧或双侧SMG硬结，与颌下腺慢性硬化性涎腺炎患者相似。Adamts 18（-/-）小鼠也表现出分泌功能障碍和严重的龋齿。组织学上，SMG硬结病的特征是进行性导管周围纤维化、腺泡萎缩、不规则导管扩张和IgG阳性浆细胞密集浸润。在Adamts 18（-/-）小鼠SMG硬结中也检测到显著的CD 4（+）T淋巴细胞和CD 11b（+）单核细胞和巨噬细胞浸润。Adamts 18（-/-）SMG中TGF-β 1、IL-6和IL-33水平显著升高，诱导慢性炎症和肌成纤维细胞活化，最终导致纤维化。这项研究表明，Adamts 18调节胚胎SMG的早期分支形态发生，并通过调节成年小鼠的局部炎症、自身免疫反应和肌成纤维细胞活化来保护自发SMG纤维形成。
Chronic sclerosing sialadenitis of the submandibular gland (also known as Kuttner tumor) is characterized by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis. The pathogenesis of this disease has been unclear, but it is associated with immune disorders. ADAMTS18 is a member of the ADAMTS superfamily of extracellular proteinases. In this study, we showed that Adamts18 is highly expressed in submandibular salivary gland (SMG) during embryonic development and decreases but is retained in adult SMG tissue in mice. Adamts18 deficiency led to reduced cleft formation and epithelial branching in embryonic SMG before embryonic day 15.5 in mice. No significant histologic changes in the later stages of branching or the morphology of SMG were detected in Adamts18(-/-) mice. However, Adamts18 deficiency causes spontaneous SMG fibrogenesis and fibrosis in adult mice. At 8 wk of age, Adamts18(-/-) mice began to manifest the first signs of pathologic changes of mild fibrosis and CD11b(+) cell infiltration in SMG tissues. At >= 8 mo, all male and female Adamts18(-/-) mice developed unilateral or bilateral SMG scleroma that is similar to patients with chronic sclerosing sialadenitis of the submandibular gland. Adamts18(-/-) mice also showed secretory dysfunction and severe dental caries. Histologically, SMG scleroma is characterized by progressive periductal fibrosis, acinar atrophy, irregular duct ectasis, and dense infiltration of IgG-positive plasma cells. A significant infiltration of CD4(+) T lymphocytes and CD11b(+) monocytes and macrophages was also detected in the SMG scleroma of Adamts18(-/-) mice. The levels of TGF-beta 1, IL-6, and IL-33 were significantly increased in Adamts18(-/-) SMGs, which induces chronic inflammation and myofibroblast activation, ultimately leading to fibrosis. This study indicates that Adamts18 regulates the early branching morphogenesis of embryonic SMG and plays a role in protecting from spontaneous SMG fibrogenesis via modulating local inflammation, autoimmune reaction, and myofibroblast activation in adult mice.