Monocytes from Sjögren's syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis

Abstract

SummarySjögren's syndrome (SS) is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction. Clinical observations and results from animal models of SS support the role of aberrant epithelial cell apoptosis and immune homeostasis loss in the glands as triggering factors for the autoimmune response. Vasoactive intestinal peptide (VIP) promotes potent anti-inflammatory effects in several inflammatory and autoimmune disease models, including the non-obese diabetic (NOD) mouse model of SS. With the knowledge that VIP modulates monocyte function through vasoactive intestinal peptide receptors (VPAC) and that immune homeostasis maintenance depends strongly upon a rapid and immunosuppressant apoptotic cell clearance by monocytes/macrophages, in this study we explored VPAC expression on monocytes from primary SS (pSS) patients and the ability of VIP to modulate apoptotic cell phagocytic function and cytokine profile. Monocytes isolated from individual pSS patients showed an increased expression of VPAC2 subtype of VIP receptors, absent in monocytes from control subjects, with no changes in VPAC1 expression. VPAC2 receptor expression could be induced further with lipopolysaccharide (LPS) in pSS monocytes and VIP inhibited the effect. Moreover, monocytes from pSS patients showed an impaired phagocytosis of apoptotic epithelial cells, as evidenced by reduced engulfment ability and the failure to promote an immunosuppressant cytokine profile. However, VIP neither modulated monocyte/macrophage phagocytic function nor did it reverse their inflammatory profile. We conclude that monocytes from pSS patients express high levels of VPAC2 and display a deficient clearance of apoptotic cells that is not modulated by VIP.

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

“…This altered expression correlates with an impaired phagocytosis of apoptotic epithelial cells, with reduced engulfment capacity and failure to express an immunosuppressant cytokine profile that is not restored by VIP. This differential expression of VPAC2 associated with phagocytic dysfunction suggests its potential as a functional biomarker in SS [303].…”

The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases

“…Also, a polymorphism in the 3 0 UTR region of the VPAC1 gene was identified in RA (Delgado et al 2008a, Paladini et al 2008. In Sjogren syndrome patients, monocytes exhibit increased VPAC2 expression and are deficient in phagocytosis of apoptotic cells (Hauk et al 2014). In contrast, reduced VPAC2 expression and a distinct DNA footprinting pattern in the VPAC2 promoter were observed in Th1 cells of MS patients (Sun et al 2006).…”

Review of autoantigens in Sjögren’s syndrome: an update

“…It has anti-inflammatory effects, as it inhibits proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and IL-6, 33 – 35 and upregulates the anti-inflammatory cytokine IL-10. 34 – 36 However, a recent study 37 has shown that exogenous VIP did not change TNF and IL-10 levels expressed by cultured MNCs that had phagocytosed apoptotic salivary gland cells obtained from pSS patients. This study did not evaluate cytokine changes in MNCs from pSS patients under other conditions.…”

“… 22 The expression of VIPR2 was recently found to be increased in monocytes from pSS patients, but unfortunately, VIPR levels were not assessed in lacrimal and meibomian glandular tissues. 37 …”

“…More interestingly, the levels of VIPR2 in pSS monocytes were restored to normal when VIP was added to the activated monocytes. 37 This reduction of VIPR2 in pSS may potentially reduce any downstream cytokine effects triggered by VIP, including those that exert anti-inflammatory effects.…”