Thrombospondin-derived peptide attenuates Sjögren's syndrome-associated ocular surface inflammation in mice.

Abstract

Sjögren's syndrome is the second most common rheumatic disease in which autoimmune response targets exocrine glands (salivary and lacrimal glands) result in clinical symptoms of dry mouth and dry eye. Inflammation of the lacrimal gland induces tear abnormalities that contribute to the inflammation of the ocular surface, which includes ocular mucosa. Thrombospondin-1 (TSP-1) plays a critical regulatory role in the ocular mucosa and as such TSP-1-/- mice develop spontaneously chronic ocular surface inflammation associated with Sjögren's syndrome. The autoimmune pathology is also accompanied by a peripheral imbalance in regulatory (Treg ) and inflammatory Th17 effectors. In this study, we demonstrate an in-vitro effect of a CD47-binding TSP-derived peptide in the induction of transforming growth factor (TGF)-β1-secreting forkhead box protein 2 (Foxp3+ ) Tregs from activated CD4+ CD25- T cells and the inhibition of pathogenic T helper type 17 (Th17)-promoting interleukin (IL)-23 derived from antigen-presenting cells. The in-vivo administration of this peptide promotes Foxp3+ Treg induction and inhibition of Th17 development. Consistent with these results, topical administration of CD47-binding TSP peptide, both before and after the onset of the disease, attenuates clinical symptoms of SS-associated dry eye in TSP-1-/- mice. Augmented expression of Foxp3 detected in the draining lymph nodes of TSP peptide -treated mice compared to those treated with control peptide suggests the ability of TSP peptide to restore peripheral immune imbalance. Thus, our results suggest that TSP-derived peptide attenuates Sjögren's syndrome-associated dry eye and autoimmune inflammation by preventing Th17 development while promoting the induction of Tregs . Collectively, our data identify TSP-derived peptide as a novel therapeutic option to treat autoimmune diseases.