Sjogren's Syndrome and TAM Receptors: A Possible Contribution to Disease Onset

Abstract

Sjogren's syndrome (SS) is a chronic, progressive autoimmune disease featuring both organ-specific and systemic manifestations, the most frequent being dry mouth and dry eyes resulting from lymphocytic infiltration into the salivary and lacrimal glands. Like the related autoimmune disease systemic lupus erythematosus (SLE), SS patients and mouse models display accumulation of apoptotic cells and a Type I interferon (IFN) signature. Receptor tyrosine kinases (RTKs) of the Tyro3, Axl, and Mer (TAM) family are present on the surface of macrophages and dendritic cells and participate in phagocytosis of apoptotic cells (efferocytosis) and inhibition of Type I IFN signaling. This review examines the relationship between TAM receptor dysfunction and SS and explores the potential contributions of TAM defects on macrophages to SS development.

Figure 1

The temporal development and onset of pSS-like disease and pathology of the C57BL/6.NOD-Aec1Aec2 mouse model. During Phase I (0-8 weeks), increased acinar cell apoptosis is detected along with elevated IFN signaling. Phase II (8-16 weeks) is characterized by an innate immune response and lymphocytic infiltration into the exocrine glands. Phase III (over 16 weeks) features an adaptive immune response with production of M3R autoantibodies and measurable loss in exocrine function. M: macrophage; T_mem: memory T cells; T_H17: T helper 17 cells; pSjS: primary Sjogren's syndrome; DC: dendritic cell; IFN: interferon; PSP: parotid secretory protein; SMX: submandibular gland; M3R: muscarinic type 3 receptor.

Figure 2

TLR and TAM receptor pathways in SS (1). Activation of TLR3 elicits the production of Type I IFN through the following transcription factors: interferon regulatory factors (IRF) 3/7, NFκB, and AP-1 (2). Type I IFN initiates Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling through the IFNAR, stimulating the expression of interferon-stimulated genes (ISGs) including TAM receptors (3). TAM receptors form a complex with IFNAR, resulting in the upregulation of SOCS3 through JAK/STAT signaling.

Figure 3

Summary of potential contributions of defective TAM signaling to SS. The etiology of SS is multifactorial, but it is known that innate immune dysfunction precedes adaptive immune dysfunction in the salivary glands. Here, we hypothesize that the TAM family of tyrosine kinases is involved in SS pathology through the TAM-mediated efferocytosis and Type I IFN regulatory pathways. We speculate that aberrations in TAM expression coupled with increased soluble Mer may account for the reported efferocytosis impairment, while downstream elements of efferocytosis signaling including Vav1 and Rac1 activation are unknown, as is SS macrophage response to IL-10 in the context of efferocytosis. Furthermore, we suggest that dysregulation of SOCS 1 and SOCS3 expression and activity may contribute to the overactive IFN signaling observed in SS. We postulate that these two failures in TAM signaling may be initial events in SS pathology that eventually lead to autoantibody generation, lymphocytic infiltration, and gland secretory dysfunction.