Ixodes ricinus Salivary Serpin IRS-2 Affects Th17 Differentiation via Inhibition of the Interleukin-6/STAT-3 Signaling Pathway

Abstract

c Th17 cells constitute a subset of CD4؉ T lymphocytes that play a crucial role in protection against extracellular bacteria and fungi. They are also associated with tissue injury in autoimmune and inflammatory diseases. Here, we report that serpin from the tick Ixodes ricinus, IRS-2, inhibits Th17 differentiation by impairment of the interleukin-6 (IL-6)/STAT-3 signaling pathway. Following activation, mature dendritic cells produce an array of cytokines, including the pleiotropic cytokine IL-6, which triggers the IL-6 signaling pathway. The major transcription factor activated by IL-6 is STAT-3. We show that IRS-2 selectively inhibits production of IL-6 in dendritic cells stimulated with Borrelia spirochetes, which leads to attenuated STAT-3 phosphorylation and finally to impaired Th17 differentiation. The results presented extend the knowledge about the effect of tick salivary serpins on innate immunity cells and their function in driving adaptive immune responses. Ticks are bloodsucking arthropods, major vectors of human pathogens like Borrelia burgdorferi and tick-borne encephalitis virus. Ticks from the family Ixodidae (hard ticks) require several days to fully engorge. During feeding, ixodid ticks remain tightly attached to their host (1, 2). To avoid attack from the host immune system during the feeding period, tick saliva contains two groups of molecules, the first with antihemostatic and the second with immunomodulatory properties. These groups include both proteinaceous and nonprotein molecules (3). One group of immunomodulatory proteins is represented by serine proteinase inhibitors (serpins), a large superfamily of structurally related, but functionally diverse, proteins that control essential proteolytic pathways (4, 5). Recently, three serine protease inhibitors, namely, purified human urinary trypsin inhibitor (UTI) and two synthetic serpins, gabextate mesilate (FOY) and nafamostat mesilate (FUT), which are widely used in treatment of acute inflammatory disorders, such as disseminated intravascular coagulation (DIC), have been shown to attenuate allergic airway inflammation and remodeling in a murine model of chronic asthma. These effects were associated with inhibition of Th2 cytokines (interleukin-4 [IL-4], IL-5, IL-6, and IL-13) and Th17 cell functions. These serpins also inhibited NF-B activation in lung tissues (6).Until now, more than 60 serpins have been identified at the sequence level in ixodid ticks, but only two serpins from Ixodes ricinus have been further functionally characterized (7-9). The first known I. ricinus serpin, Iris (I. ricinus immunosuppressor), is known to preferentially target leukocyte elastase. It also interferes with the contact phase coagulation pathway, fibrinolysis, and disrupts platelet adhesion. Moreover, Iris has the ability to modulate both innate and adaptive immunity. It affects T lymphocyte and macrophage responsiveness, and it induces a Th2-type response and inhibits the production of proinflammatory cytokines. Interestingly, it was shown that the anti-inf...

Serpins in arthropod biology

“…Inhibition of cathepsin G and thrombin also contribute to the blocking of platelet aggregation by IRS-2 [108]. Furthermore, recent data demonstrate that IRS-2 can interfere with adaptive immune responses [109]. IRS-2 inhibits IL-6 production by dendritic cells stimulated with Borellia spirochetes, and primary neutrophils.…”

Heparan sulfate/heparin glycosaminoglycan binding alters inhibitory profile and enhances anticoagulant function of conserved Amblyomma americanum tick saliva serpin 19

“…Several studies have established that some tick saliva serpins have inhibitory functions against host defense system proteases (Chmelar et al, 2011; Ibelli et al, 2014; Kim et al, 2015; Mulenga et al, 2013; Prevot et al, 2006, 2009; Xu et al, 2016). Other studies have shown that some of tick saliva serpins can delay blood clotting (Ibelli et al, 2014; Kim et al, 2015; Mulenga et al, 2013), prevent platelet aggregation (Chmelar et al, 2011; Ibelli et al, 2014; Kim et al, 2015; Mulenga et al, 2013), and block inflammation (Prevot et al, 2009) and host immune response (Palenikova et al, 2015). …”

For Whom the Bell Tolls (and Nods): Spit-acular Saliva

“…Some specific salivary molecules have been characterized in the context of B. burgdorferi infection. These include: Salp15 (binds to outer surface protein C [OspC] on the spirochete and protects it from antibody-mediated killing) [46], Salp25D (inhibits the complement system) [47], P8 (inhibits the lectin complement pathway) [48], IRS-2 (prevents Th17 differentiation by inhibiting IL-6/STAT-3 signaling pathway in dendritic cells) [49] and sialostatin L2 (facilitates B. burgdorferi population expansion in the skin) [50]. …”