Adamts18 Deficiency Causes Spontaneous SMG Fibrogenesis in Adult Mice

Area of Science:

• Biochemistry and Molecular Biology
• Developmental Biology
• Immunology

Background:

• Chronic sclerosing sialadenitis (Küttner tumor) is a submandibular gland swelling linked to immune disorders, with unclear pathogenesis.
• ADAMTS18, an extracellular proteinase, has an unknown role in salivary gland development and disease.

Purpose of the Study:

• To investigate the role of ADAMTS18 in submandibular gland (SMG) development and its involvement in spontaneous fibrogenesis.
• To elucidate the molecular mechanisms underlying SMG fibrosis in Adamts18-deficient mice.

Main Methods:

• Analysis of Adamts18 expression in mouse SMG during development and adulthood.
• Histological and immunohistochemical examination of SMG from wild-type and Adamts18^-/- mice at various ages.
• Measurement of inflammatory and fibrotic markers (TGF-β1, IL-6, IL-33, CD4+, CD11b+ cells) in SMG tissues.

Main Results:

• Adamts18 deficiency impaired embryonic SMG branching morphogenesis but did not affect later development.
• Adamts18^-/- mice spontaneously developed SMG fibrogenesis and scleroma resembling chronic sclerosing sialadenitis in adulthood.
• Increased TGF-β1, IL-6, and IL-33 levels, along with immune cell infiltration, were observed in the SMGs of deficient mice, driving fibrosis.

Conclusions:

• ADAMTS18 is essential for early embryonic SMG branching.
• ADAMTS18 deficiency leads to spontaneous SMG fibrosis and scleroma in adult mice by promoting inflammation and myofibroblast activation.
• ADAMTS18 plays a protective role against the development of chronic sclerosing sialadenitis-like pathology in the submandibular gland.