PMID- 32766239 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210615 IS - 2296-634X (Print) IS - 2296-634X (Electronic) IS - 2296-634X (Linking) VI - 8 DP - 2020 TI - 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. PG - 554 LID - 10.3389/fcell.2020.00554 [doi] LID - 554 AB - 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. CI - Copyright (c) 2020 Zhou, Tahir, Wang, Woodson, Sherman, Karim, Neelakanta and Sultana. FAU - Zhou, Wenshuo AU - Zhou W AD - Department of Biological Sciences, Old Dominion University, Norfolk, VA, United States. FAU - Tahir, Faizan AU - Tahir F AD - Center for Molecular and Cellular Biosciences, School of Biological, Environmental, and Earth Sciences, The University of Southern Mississippi, Hattiesburg, MS, United States. FAU - Wang, Joseph Che-Yen AU - Wang JC AD - Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, United States. AD - Electron Microscopy Center, Indiana University, Bloomington, IN, United States. FAU - Woodson, Michael AU - Woodson M AD - Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States. FAU - Sherman, Michael B AU - Sherman MB AD - Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX, United States. AD - Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch at Galveston, Galveston, TX, United States. FAU - Karim, Shahid AU - Karim S AD - Center for Molecular and Cellular Biosciences, School of Biological, Environmental, and Earth Sciences, The University of Southern Mississippi, Hattiesburg, MS, United States. FAU - Neelakanta, Girish AU - Neelakanta G AD - Department of Biological Sciences, Old Dominion University, Norfolk, VA, United States. AD - Center for Molecular Medicine, Old Dominion University, Norfolk, VA, United States. FAU - Sultana, Hameeda AU - Sultana H AD - Department of Biological Sciences, Old Dominion University, Norfolk, VA, United States. AD - Center for Molecular Medicine, Old Dominion University, Norfolk, VA, United States. AD - Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States. LA - eng GR - P20 GM103476/GM/NIGMS NIH HHS/United States GR - R01 AI141790/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20200716 PL - Switzerland TA - Front Cell Dev Biol JT - Frontiers in cell and developmental biology JID - 101630250 PMC - PMC7378379 OTO - NOTNLM OT - C-X-C motif chemokine ligand 12 (CXCL12) OT - exosomes OT - interleukin-8 (IL-8) OT - saliva OT - salivary glands OT - skin barrier OT - ticks OT - wound healing EDAT- 2020/08/09 06:00 MHDA- 2020/08/09 06:01 PMCR- 2020/01/01 CRDT- 2020/08/09 06:00 PHST- 2019/11/10 00:00 [received] PHST- 2020/06/10 00:00 [accepted] PHST- 2020/08/09 06:00 [entrez] PHST- 2020/08/09 06:00 [pubmed] PHST- 2020/08/09 06:01 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fcell.2020.00554 [doi] PST - epublish SO - Front Cell Dev Biol. 2020 Jul 16;8:554. doi: 10.3389/fcell.2020.00554. eCollection 2020.