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Theranostics 2023; 13(12):4059-4078. doi:10.7150/thno.84935 This issue Cite

Research Paper

Soluble CD93 lectin-like domain sequesters HMGB1 to ameliorate inflammatory diseases

Shang-En Huang¹, Cheng-Hsiang Kuo², Si-Yu Shiao^3,4, Chia-Rui Shen⁵, Fang-Tzu Lee^4,6, Bi-Ing Chang^3,4, Jong-Hau Hsu^1,7,8, Hua-Lin Wu^2,3,4, Jwu-Lai Yeh^1,9,10,11✉, Chao-Han Lai^3,4,6,12✉

1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
2. International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
3. Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
4. Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.
5. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
6. Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
7. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
8. Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
9. Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
10. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
11. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
12. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

✉ Corresponding authors: Chao-Han Lai, MD, PhD, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 138, Sheng-Li Road, Tainan 70403, Taiwan. Tel: 886-6-2353535 ext. 3264; Fax: 886-6-2766676; E-mail: d303878hosp.ncku.edu.tw. Jwu-Lai Yeh, PhD, Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, 100 Shih-Chuan First Road, Kaohsiung 807, Taiwan. Tel: 886-7-3121101 ext. 2139; Fax: 886-7-3234686; E-mail: jwulaiedu.tw. More

Abstract

Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (sCD93) upon inflammatory stimuli. sCD93 effectively enhances apoptotic cell clearance and has been proposed as an inflammatory disease biomarker. The function of sCD93 involved directly in inflammation remains to be determined. Herein, we attempted to examine the hypothesis that sCD93 might sequester proinflammatory high-mobility group box 1 protein (HMGB1), exerting anti-inflammatory properties.

Methods: Different forms of soluble recombinant human CD93 (rCD93) were prepared by a mammalian protein expression system. rCD93-HMGB1 interaction was assessed using co-immunoprecipitation and solid-phase binding assays. Effects of soluble rCD93 were evaluated in HMGB1-induced macrophage and vascular smooth muscle cells (VSMC) activation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, CaCl₂-induced and angiotensin II-infused abdominal aortic aneurysm (AAA) formation and ovariectomized-induced osteoporosis in mice.

Results: Protein binding studies revealed that soluble rCD93, via the lectin-like domain (D1), can bind to HMGB1 and intercept HMGB1-receptor interaction. Soluble rCD93 containing D1 inhibited HMGB1-induced proinflammatory cytokine production and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation in macrophages and VSMCs, thereby attenuating CaCl₂-induced and angiotensin II-infused AAA models. During osteoclastogenesis, RANKL stimulated HMGB1 secretion that promoted RANKL-induced osteoclastogenesis in return. Soluble rCD93 containing D1 impeded RANKL-induced osteoclastogenic marker gene expression and intracellular MAPK/NF-κB signaling, thereby mitigating ovariectomized-induced osteoporosis.

Conclusion: These findings demonstrate the therapeutic potential of soluble recombinant CD93 containing D1 in inflammatory diseases. Our study highlights a novel anti-inflammatory mechanism, i.e., sequestration of HMGB1, through which sCD93 prevents HMGB1-receptor interaction on effector cells and alleviates inflammation.

Keywords: CD93, high-mobility group box 1 (HMGB1) protein, inflammation, abdominal aortic aneurysm, osteoporosis

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