Agonistic anti-DCIR antibody inhibits ITAM-mediated inflammatory signaling and promotes immune resolution
Liang Chen, Suresh Patil, Jeffrey Barbon, James Waire, Stephen Laroux, Donna McCarthy, Mishra Pratibha, Suju Zhong, Feng Dong, Karin Orsi, Gunarso Nguyen, Yingli Yang, Nancy Crosbie, Eric Dominguez, Arun Deora, Geertruida Veldman, Susan Westmoreland, Liang Jin, Timothy Radstake, Kevin White, Hsi-Ju Wei
Liang Chen, Suresh Patil, Jeffrey Barbon, James Waire, Stephen Laroux, Donna McCarthy, Mishra Pratibha, Suju Zhong, Feng Dong, Karin Orsi, Gunarso Nguyen, Yingli Yang, Nancy Crosbie, Eric Dominguez, Arun Deora, Geertruida Veldman, Susan Westmoreland, Liang Jin, Timothy Radstake, Kevin White, Hsi-Ju Wei
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Research Article Immunology

Agonistic anti-DCIR antibody inhibits ITAM-mediated inflammatory signaling and promotes immune resolution

Abstract

DC inhibitory receptor (DCIR) is a C-type lectin receptor selectively expressed on myeloid cells, including monocytes, macrophages, DCs, and neutrophils. Its role in immune regulation has been implicated in murine models and human genome-wide association studies, suggesting defective DCIR function associates with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus, and Sjögren’s syndrome. However, little is known about the mechanisms underlying DCIR activation to dampen inflammation. Here, we developed anti-DCIR agonistic antibodies that promote phosphorylation on DCIR’s immunoreceptor tyrosine-based inhibitory motifs and recruitment of SH2 containing protein tyrosine phosphatase-2 for reducing inflammation. We also explored the inflammation resolution by depleting DCIR+ cells with antibodies. Utilizing a human DCIR–knock-in mouse model, we validated the antiinflammatory properties of the agonistic anti-DCIR antibody in experimental peritonitis and colitis. These findings provide critical evidence for targeting DCIR to develop transformative therapies for inflammatory diseases.

Authors

Liang Chen, Suresh Patil, Jeffrey Barbon, James Waire, Stephen Laroux, Donna McCarthy, Mishra Pratibha, Suju Zhong, Feng Dong, Karin Orsi, Gunarso Nguyen, Yingli Yang, Nancy Crosbie, Eric Dominguez, Arun Deora, Geertruida Veldman, Susan Westmoreland, Liang Jin, Timothy Radstake, Kevin White, Hsi-Ju Wei

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Figure 5

Agonistic anti-DCIR mAb ameliorates experimental acute peritonitis.

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Agonistic anti-DCIR mAb ameliorates experimental acute peritonitis. (A) ...
(A) Study design of the prophylactic anti-DCIR mAbs treatment in the ZymD-induced peritonitis model. Anti-DCIR mAbs and Fc-matched isotype control were i.p. injected into the mice 1 day before the i.p. administration of 0.5 mL 2 mg/mL ZymD to induce peritonitis. (B–G) Relative leukocyte and neutrophil infiltration (B and C) and cytokine production in the peritoneal lavage (D–G) collected from the mice received i.p. administration of 10 mpk anti-DCIR mAbs clone 9D9 (n = 6 huDCIR-KI mice), 3A4 (n = 4 WT or n = 22 huDCIR-KI mice), 3F7 (n = 6 huDCIR-KI mice), or isotype (n = 5 WT or 14 huDCIR-KI mice) in the peritonitis model as described in A. (H–M) Relative leukocytes and neutrophils infiltration (H and I) and cytokine production in the peritoneal lavage (J–M) isolated from the mice received 10 mpk i.p. administration of agonistic anti-DCIR mAb clone 3A4 with WT (n = 22) or LALA (L234A and L235A) mutant huIgG1 Fc (n = 6) or isotype (n = 31) in the peritonitis model as described in A. Data are normalized to the isotype group. Each datum represents an individual mouse treated with indicated condition. Means ± SEM are shown, and statistical significance is determined by 1-way ANOVA test with Dunnett’s correction for multiple comparison to the isotype treated condition. *P < 0.05, **P < 0.01, ***P < 0.001.