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

Piper A. Robida, Clayton H. Rische, Netali Ben Baruch Morgenstern, Rethavathi Janarthanam, Yun Cao, Rebecca A. Krier-Burris, Wouter Korver, Alan Xu, Thuy Luu, Julia Schanin, John Leung, Marc E. Rothenberg, Joshua B. Wechsler, Bradford A. Youngblood, Bruce S. Bochner, Jeremy A. O’Sullivan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number1138
Issue number7
StatePublished - Apr 1 2022


  • FcεRI
  • ITIM
  • Siglec-6
  • degranulation
  • endocytosis
  • mast cell
  • signaling

ASJC Scopus subject areas

  • Medicine(all)


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