The role of extracellular DNA traps in the development of sialadenitis and primary Sjögren´s Syndrome

• Applicant: Privatdozent Dr. Luis Munoz, Ph.D.
• Subject Area: Rheumatology ; Otolaryngology, Phoniatrics and Audiology ; Clinical Immunology and Allergology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470134687

Neutrophil extracellular traps (NETs) can be found on healthy mucosal surfaces and glandular ducts. Its aggregation to larger clusters (aggNETs) in exocrine ducts can induce damage of glandular epithelial cells. The cellular and molecular mechanisms that lead to a breakdown of self-tolerance of salivary tissues have been associated with subtle early damage of salivary epithelial cells. The migration of neutrophils and NETs formation are finely tuned by the autonomous nerve system, especially through the beta-adrenergic receptors. Therefore, the applicant sought to study in a beta-adrenergic induced sialadenitis model the role of NETs in the development of primary lesions of salivary epithelial cells and its contribution to the establishment of tertiary lymphoid organs and primary Sjögren´s syndrome (pSS). Gene expression at the single cell level in epithelial cells and immunofibroblasts will be evaluated during active sialadenitis and after recovery. The role of NETs during sialadenitis will be studied in mouse strains deficient for NET formation (PADi4-/- and Ncf1**) and the modulation of NET formation by the beta-adrenergic axis will be assessed in mouse strains deficient for the beta-adrenergic receptors (Adbr1-/- and Adbr2-/-). The specific influence of beta-adrenergic stimulation on the immune system will be tested in bone marrow transplanted animals bearing leukocytes deficient for one of these receptors. In a further approach, the applicant intend to retard the onset of spontaneous pSS in the susceptible strain NOD.B10.H2b by interfering with glandular neutrophil migration and NET formation employing specific beta-adrenergic blockers and inhibitors of the NET formation, respectively.

• DFG Programme: Research Grants