Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide

Sjögren's syndrome is a multifactorial systemic autoimmune disorder characterized by lymphocytic infiltrates in exocrine organs. Patients present with sicca symptoms, such as extensive dry eyes and dry mouth, and parotid enlargement. Other serious complications include profound fatigue, chronic pain, major organ involvement, neuropathies and lymphomas. Current treatments only focus on relieving symptoms and do not target the origin of the disease, which is largely unknown. The question we addressed here was whether some defects exist in Autophagy processes in Sjögren's syndrome and if they can be corrected or minimized using an appropriate mechanism-driven treatment targeting this central survival pathway. Using a recognized murine model of secondary Sjögren's syndrome, we identified molecular alterations of Autophagy occurring in the salivary glands of MRL/lpr mice, and discovered that opposite (up- or down-regulated) Autophagy events can arise in distinct organs of the same mouse strain, here in lymphoid organs and salivary glands. We showed further that the therapeutic P140 peptide, known to directly act on chaperone-mediated Autophagy, rescued MRL/lpr mice from cellular infiltration and Autophagy defects occurring in salivary glands. Our findings provide a proof-of-concept that targeting Autophagy might represent a promising therapeutic strategy for treating patients with Sjögren's syndrome.

Autophagy; Lysosomal dysfunction; MRL/lpr mice; P140 peptide; Salivary glands; Sjögren's syndrome.