Release of Luminal Exosomes Contributes to TLR4-Mediated Epithelial Antimicrobial Defense

PLoS Pathogens

Amanda L. Roth¹  Ai-Yu Gong¹  Xian-Ming Chen¹  Nancy D. Hanson¹  Guoku Hu¹  Guan Zhu²  Nicholas F. LaRusso³  Bing Q. Huang³  Honorine D. Ward⁴ 

[1] Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, United States of America;Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America;Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America;Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, United States of America

关键词: Exosomes;    Cryptosporidium parvum;    Sporozoites;    Epithelial cells;    MicroRNAs;    Immune receptor signaling;    Phosphorylation;    Parasitic diseases;   

DOI  :  10.1371/journal.ppat.1003261

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Exosomes are membranous nanovesicles released by most cell types from multi-vesicular endosomes. They are speculated to transfer molecules to neighboring or distant cells and modulate many physiological and pathological procedures. Exosomes released from the gastrointestinal epithelium to the basolateral side have been implicated in antigen presentation. Here, we report that luminal release of exosomes from the biliary and intestinal epithelium is increased following infection by the protozoan parasite Cryptosporidium parvum. Release of exosomes involves activation of TLR4/IKK2 signaling through promoting the SNAP23-associated vesicular exocytotic process. Downregulation of let-7 family miRNAs by activation of TLR4 signaling increases SNAP23 expression, coordinating exosome release in response to C. parvum infection. Intriguingly, exosomes carry antimicrobial peptides of epithelial cell origin, including cathelicidin-37 and beta-defensin 2. Activation of TLR4 signaling enhances exosomal shuttle of epithelial antimicrobial peptides. Exposure of C. parvum sporozoites to released exosomes decreases their viability and infectivity both in vitro and ex vivo. Direct binding to the C. parvum sporozoite surface is required for the anti-C. parvum activity of released exosomes. Biliary epithelial cells also increase exosomal release and display exosome-associated anti-C. parvum activity following LPS stimulation. Our data indicate that TLR4 signaling regulates luminal exosome release and shuttling of antimicrobial peptides from the gastrointestinal epithelium, revealing a new arm of mucosal immunity relevant to antimicrobial defense.

【 授权许可】

CC BY