A link between interferon and augmented plasmin generation in exocrine gland damage in Sjögren's syndrome

Abstract

Sjögren’s syndrome is an autoimmune disease that targets exocrine glands, but often exhibits systemic manifestations. Infiltration of the salivary and lacrimal glands by lymphoid and myeloid cells orchestrates a perpetuating immune response leading to exocrine gland damage and dysfunction. Th1 and Th17 lymphocyte populations and their products recruit additional lymphocytes, including B cells, but also large numbers of macrophages, which accumulate with disease progression. In addition to cytokines, chemokines, chitinases, and lipid mediators, macrophages contribute to a proteolytic milieu, underlying tissue destruction, inappropriate repair, and compromised glandular functions. Among the proteases enhanced in this local environment are matrix metalloproteases (MMP) and plasmin, generated by plasminogen activation, dependent upon plasminogen activators, such as tissue plasminogen activator (tPA). Not previously associated with salivary gland pathology, our evidence implicates enhanced tPA in the context of inflamed salivary glands revolving around lymphocyte-mediated activation of macrophages. Tracking down the mechanism of macrophage plasmin activation, the cytokines IFNγ and to a lesser extent, IFNα, via Janus kinase (JAK) and signal transducer and activator of transcription (STAT) activation, were found to be pivotal for driving the plasmin cascade of proteolytic events culminating in perpetuation of the inflammation and tissue damage, and suggesting intervention strategies to blunt irreversible tissue destruction.

Expression of interleukin‐17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta‐analysis

“…75 In addition, IL-17 could stimulate the release of matrix metalloproteinases, destroying components of the extracellular matrix and resulting in compromised function of the exocrine glands. 76,77 In recent years, several articles have explored the aberrant expression of IL-17 in patients with pSS. The aim of this comprehensive meta-analysis is to clarify alterations of IL-17 in the serum, tears, saliva and salivary glands of patients with pSS, as well as its correlation with disease severity.…”

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

“…In many cell types, SERPINB2 is strongly upregulated during inflammation, infection, tissue damage and other diseased conditions . However, the role of SERPINB2 in the skin is not well understood.…”

The true nature of salivary NGF

“…It is known that pro-NGF released from the nerve fibers is processed by proteolytic cleavage by MMP2 (Saygili et al, 2011) and plasmin (Srinivasan et al, 2004). Both MMP2 (G€ ursoy et al, 2010) and plasmin (Gliozzi et al, 2013) are present in saliva. However, saliva also contains proteinase inhibitors such as TIMPs (Pietruska et al, 2009;G€ ursoy et al, 2010).…”