Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells

Cells

Wouter Korver¹  Thuy Luu¹  Alan Xu¹  Bradford A. Youngblood¹  John Leung¹  Julia Schanin¹  Bruce S. Bochner²  Yun Cao²  Rebecca A. Krier-Burris²  Joshua B. Wechsler²  Piper A. Robida²  Jeremy A. O’Sullivan²  Netali Ben-Baruch Morgenstern³  Marc E. Rothenberg³  Rethavathi Janarthanam⁴  Clayton H. Rische⁵ 

[1] Allakos, Inc., Redwood City, CA 94065, USA;Division of Allergy and Immunology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA;McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA;

关键词: mast cell;    Siglec-6;    FcεRI;    degranulation;    ITIM;    endocytosis;   

DOI  :  10.3390/cells11071138

来源: DOAJ

【 摘 要 】

Mast cells are tissue-resident cells that contribute to allergic diseases, among others, due to excessive or inappropriate cellular activation and degranulation. Therapeutic approaches to modulate mast cell activation are urgently needed. Siglec-6 is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptor selectively expressed by mast cells, making it a promising target for therapeutic intervention. However, the effects of its engagement on mast cells are poorly defined. Siglec-6 expression and endocytosis on primary human mast cells and mast cell lines were assessed by flow cytometry. SIGLEC6 mRNA expression was examined by single-cell RNAseq in esophageal tissue biopsy samples. The ability of Siglec-6 engagement or co-engagement to prevent primary mast cell activation was determined based on assessments of mediator and cytokine secretion and degranulation markers. Siglec-6 was highly expressed by all mast cells examined, and the SIGLEC6 transcript was restricted to mast cells in esophageal biopsy samples. Siglec-6 endocytosis occurred with delayed kinetics relative to the related receptor Siglec-8. Co-crosslinking of Siglec-6 with FcεRIα enhanced the inhibition of mast cell activation and diminished downstream ERK1/2 and p38 phosphorylation. The selective, stable expression and potent inhibitory capacity of Siglec-6 on human mast cells are favorable for its use as a therapeutic target in mast cell-driven diseases.

【 授权许可】

Unknown