Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the GM-CSF-STAT5 pathway

Haiyang Sun; Ce Tang; Soo-Hyun Chung; Xiao-Qi Ye; Yulia Makusheva; Wei Han; Masato Kubo; Shigeyuki Shichino; Satoshi Ueha; Koji Matsushima; Kazuho Ikeo; Masahide Asano; Yoichiro Iwakura

doi:10.1016/j.celrep.2022.111158

Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the GM-CSF-STAT5 pathway

Cell Rep. 2022 Aug 2;40(5):111158. doi: 10.1016/j.celrep.2022.111158.

Authors

Affiliations

¹ Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan.
² Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, Guangdong Province 510080, China.
³ Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
⁴ Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
⁵ DNA Data Analysis Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
⁶ Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
⁷ Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan. Electronic address: iwakura@rs.tus.ac.jp.

PMID: 35926458
DOI: 10.1016/j.celrep.2022.111158

Abstract

Dendritic cell immunoreceptor (DCIR; Clec4a2), a member of the C-type lectin receptor family, plays important roles in homeostasis of the immune and bone systems. However, the intestinal role of this molecule is unclear. Here, we show that dextran sodium sulfate (DSS)-induced colitis and azoxymethane-DSS-induced intestinal tumors are reduced in Clec4a2^-/- mice independently of intestinal microbiota. STAT5 phosphorylation and expression of Csf2 and tight junction genes are enhanced, while Il17a and Cxcl2 are suppressed in the Clec4a2^-/- mouse colon, which exhibits reduced infiltration of neutrophils and myeloid-derived suppressor cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) administration ameliorates DSS colitis associated with reduced Il17a and enhanced tight junction gene expression, whereas anti-GM-CSF exacerbates symptoms. Furthermore, anti-NA2, a ligand for DCIR, ameliorates colitis and prevents colorectal tumors. These observations indicate that blocking DCIR signaling ameliorates colitis and suppresses colonic tumors, suggesting DCIR as a possible target for the treatment of these diseases.

Keywords: CP: Cancer; CP: Cell biology; CXCL2; GM-CSF; STAT5; colitis; colorectal tumors; dendritic cell immunoreceptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colitis* / pathology
Colorectal Neoplasms*
Dextran Sulfate
Disease Models, Animal
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
Lectins, C-Type / genetics
Lectins, C-Type / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
STAT5 Transcription Factor / metabolism

Substances

Dcir protein, mouse
Lectins, C-Type
STAT5 Transcription Factor
Granulocyte-Macrophage Colony-Stimulating Factor
Dextran Sulfate