Discovery of Exosomes From Tick Saliva and Salivary Glands Reveals Therapeutic Roles for CXCL12 and IL-8 in Wound Healing at the Tick–Human Skin Interface

Abstract

Ticks secrete various anti-coagulatory, anti-vasoconstrictory, anti-inflammatory, and anti-platelet aggregation factors in their saliva at the bite site during feeding to evade host immunological surveillance and responses. For the first time, we report successful isolation of exosomes (small membrane-bound extracellular signaling vesicles) from saliva and salivary glands of partially fed or unfed ixodid ticks. Our data showed a novel role of these in vivo exosomes in the inhibition of wound healing via downregulation of C-X-C motif chemokine ligand 12 (CXCL12) and upregulation of interleukin-8 (IL-8). Cryo-electron microscopy (cryo-EM) analysis revealed that tick saliva and salivary glands are composed of heterogeneous populations of in vivo exosomes with sizes ranging from 30 to 200 nm. Enriched amounts of tick CD63 ortholog protein and heat shock protein 70 (HSP70) were evident in these exosomes. Treatment of human skin keratinocytes (HaCaT cells) with exosomes derived from tick saliva/salivary glands or ISE6 cells dramatically delayed cell migration, wound healing, and repair process. Wound healing is a highly dynamic process with several individualized processes including secretion of cytokines. Cytokine array profiling followed by immunoblotting and quantitative-PCR analysis revealed that HaCaT cells treated with exosomes derived from tick saliva/salivary glands or ISE6 cells showed enhanced IL-8 levels and reduced CXCL12 loads. Inhibition of IL-8 or CXCL12 further delayed exosome-mediated cell migration, wound healing, and repair process, suggesting a skin barrier protection role for these chemokines at the tick bite site. In contrast, exogenous treatment of CXCL12 protein completely restored this delay and enhanced the repair process. Taken together, our study provides novel insights on how tick salivary exosomes secreted in saliva can delay wound healing at the bite site to facilitate successful blood feeding.

Changing the Recipe: Pathogen Directed Changes in Tick Saliva Components

“…Extracellular vesicles are small lipid blebs that secrete for cell-to-cell communication. Extracellular vesicles have been detected in the saliva of I. scapularis, Amblyomma maculatum, and H. longicornis [145][146][147]. Vesicles from H. longicornis contain known protein effectors, like lipocalins, cement-like proteins, and serpins as well as novel miRNAs suspected to influence host immune responses [145,146].…”

“…Vesicles from H. longicornis contain known protein effectors, like lipocalins, cement-like proteins, and serpins as well as novel miRNAs suspected to influence host immune responses [145,146]. Furthermore, in vitro experiments indicate that vesicles from I. scapularis and A. maculatum diminish chemokine and cytokine secretion and delay wound healing responses [147]. Several studies have shown their immunomodulating effects and influence on infection by several vector-borne pathogens [148], including the transmission of Langat virus (LGTV) from tick cells to mammalian cells [149].…”

“…scapularis and A . maculatum diminish chemokine and cytokine secretion and delay wound healing responses [ 147 ]. Several studies have shown their immunomodulating effects and influence on infection by several vector-borne pathogens [ 148 ], including the transmission of Langat virus (LGTV) from tick cells to mammalian cells [ 149 ].…”

Evaluation of Wound Healing Activity of Catharanthus Roseus Aqueous Extract in Adult Albino Rats

“…The results obtained for CE was comparable to that of the standard sucralfate showing increased percentage of wound closure and reduced time for complete epithelialization. This reduced duration for wound healing can be due to the release of one of the inflammatory chemokineinterleukin-8 that plays a significant role in the recruitment of inflammatory cells such as keratinocytes and fibroblasts 26 . This in turn leads to an elevation in the intracellular communication within the fibroblasts.…”

Composition and Clinical Significance of Exosomes in Tuberculosis: A Systematic Literature Review

“…Exosomes are different in origin, size, and content and involved in the pathogenesis of infection [ 9 ]. Studies performed over the past years proved that exosomes exist in almost all biological fluids [ 10 , 11 ], including plasma [ 12 , 13 ], serum [ 14 ], bovine and human milk [ 15 ], urine [ 16 ], and saliva [ 17 ]. Importantly, an increasing evidence suggests that exosomes play critical role in cell-to-cell communication [ 18 , 19 ], including the interaction between microorganisms and infected human cells.…”