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

Frontiers in Cell and Developmental Biology

Girish Neelakanta¹  Shahid Karim²  Faizan Tahir²  Michael Woodson³  Wenshuo Zhou⁴  Hameeda Sultana⁶  Joseph Che-Yen Wang⁷  Michael B. Sherman⁸ 

[1] Center for Molecular Medicine, Old Dominion University, Norfolk, VA, United States;Center for Molecular and Cellular Biosciences, School of Biological, Environmental, and Earth Sciences, The University of Southern Mississippi, Hattiesburg, MS, United States;Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States;Department of Biological Sciences, Old Dominion University, Norfolk, VA, United States;Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, United States;Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States;Electron Microscopy Center, Indiana University, Bloomington, IN, United States;Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch at Galveston, Galveston, TX, United States;

关键词: exosomes;    ticks;    saliva;    salivary glands;    interleukin-8 (IL-8);    C-X-C motif chemokine ligand 12 (CXCL12);   

DOI  :  10.3389/fcell.2020.00554

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown