Tick saliva induces regulatory dendritic cells: MAP-kinases and Toll-like receptor-2 expression as potential targets

Abstract

Ticks (Acari: Ixodidae) are bloodsucking ectoparasitic arthropods of human and veterinary medical importance. Tick saliva has been shown to contain a wide range of bioactive molecules with vasodilatory, antihemostatic, and immunomodulatory activities. We have previously demonstrated that saliva from Rhipicephalus sanguineus ticks inhibits the maturation of dendritic cells (DCs) stimulated with LPS. Here we examined the mechanism of this immune subversion, evaluating the effect of tick saliva on Toll-like receptor (TLR)-4 signalling pathway in bone marrow-derived DCs. We demonstrated that R. sanguineus tick saliva impairs maturation of DCs stimulated with LPS, a TLR-4 ligand, leading to increased production of interleukin (IL)-10 and reduced synthesis of IL-12p70 and TNF-alpha. The immunomodulatory effect of the tick saliva on the production of pro-inflammatory cytokines by DCs stimulated with LPS was associated with the observation that tick saliva inhibits the activation of the ERK 1/2 and p38 MAP kinases. These effects were independent of the expression of TLR-4 on the surface of DCs. Additionally, saliva-treated DCs also presented a similar pattern of cytokine modulation in response to other TLR ligands. Since the recent literature reports that several parasites evade immune responses through TLR-2-mediated production of IL-10, we evaluated the effect of tick saliva on the percentage of TLR-2(+) DCs stimulated with the TLR-2 ligand lipoteicoic acid (LTA). The data showed that the population of DCs expressing TLR-2 was significantly increased in DCs treated with LTA plus saliva. In addition, tick saliva alone increased the expression of TLR-2 in a dose- and time-dependent manner. Our data suggest that tick saliva induces regulatory DCs, which secrete IL-10 and low levels of IL-12 and TNF-alpha when stimulated by TLR ligands. Such regulatory DCs are associated with expression of TLR-2 and inhibition of ERK and p38, which promotes the production of IL-10 and thus down-modulates the host's immune response, possibly favouring susceptibility to tick infestations.

Association of bovine Toll-like receptor 4 with tick infestation rates and blood histamine concentration

“…Oliveira et al (2010) have summarized the six categories of active molecules from the salivary glands of ticks: 1) prostaglandin (Bowman et al, 1995); 2) histamine band proteins (Arocha-Pinango et al, 1999); 3) platelet aggregation inhibitor (Mans et al, 2002); 4) thrombin inhibitor (Liao et al, 2009); 5) antimicrobial protein (Lai et al, 2004b); and 6) an opioid peptide analog identified from neuroganglion, which is believed to inhibit algesthesia in the host (Lai et al, 2004a,b). The domain that mediates inflammation in the allergic reaction caused by these bioactive molecules is histamine.…”

“…In contrast, the preinfested Indian cattle presented a response between 10 min and 1 h post-inoculation as well as a delayed reaction 72 h post-injection. Bioactive molecules in tick saliva have been shown to stimulate a TLR4 ligand, leading to increased secretion of interleukin-10 and initiate immune response (Oliveira et al, 2010). After a 6-week infestation with B. microplus, cattle that were more susceptible to tick infestation showed more obvious engorgement and granulocyte infiltrations at bite sites compared with those in cattle that were less susceptible to tick infestation; the host limited the inflammatory process, which contributed to the resolution of inflammation and wound healing (Constantinoiu et al, 2010).…”

“…These biofactors may inhabit the maturation of dendritic cells. Stimulated dendritic cells generate lipopolysaccharide, the ligand of TLR4, and ultimately weaken host immunity, making them more sensitive to tick infestation (Oliveira et al, 2010). TLR2-deficit mice are more sensitive to Mycobacterium tuberculosis, and the capacity of TLR4-deficit mice to eradicate M. tuberculosis significantly declines in chronic infection, suggesting a domain function for TLR4 in chronic infection (Abel et al, 2002;Reiling et al, 2002).…”

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

“…By first enhancing uptake with TLR-L, the DC might become resistant to cytokines due to the activation of SOCS1/2, resulting in disturbed maturation. Moreover, TLR-mediated induction of maturation-inhibitory cytokines (e.g., IL-10) might be responsible for this maturation inhibitory effect [44, 45]. We did the attempt inhibition of putatively involved down-stream signaling elements (a.o.…”

Modulation of host immunity by tick saliva

“…Tick saliva also inhibited the chemokine RANTES by reducing expression of its surface receptor CCR5 [74]. DC maturation was impaired via toll-like receptor (TLR) signaling [75]. However, the inhibition of migration was limited to immature DCs.…”