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HMGB1 Inhibitor Effectively Alleviates Psoriasis-Like Lesions and Inflammatory Cytokines in K14-VEGF Transgenic Mice

国际皮肤性病学杂志(英文),2023, 06 (01): 9-14.
Objective:

Anti-high-mobility group box 1 (HMGB1) is involved in the pathogenesis of many inflammatory and autoimmune diseases, including psoriasis. The present study aimed to investigate the therapeutic effects of HMGB1 monoclonal antibody (mAb) in keratin 14 (K14)-vascular endothelial growth factor (VEGF) transgenic homozygous mice.

Methods:

Twelve VEGF transgenic mice were randomly divided into two groups of six mice each: the anti-HMGB1 mAb group and the immune complex (IC) mAb group. The mice underwent intraperitoneal injection of anti-HMGB1 mAb or IC mAb once every 2 days for a total of three treatments. Compare the lesions on the ears of the mice and evaluate the severity of the lesions using the baseline and clinical scores on the last day of treatment. The changes in psoriasis-like lesions, cellular infiltration of T cells, dendritic cells, and neutrophils were detected by hematoxylin-eosin staining and immunohistochemistry. The mRNA expression of the inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, interferon-γ, and IL-17 in the lesions were assessed by real-time quantitative polymerase chain reaction. The number of γδ T cells in the lesions of two groups were detected by flow cytometry. The t test was used to compare their differences.

Results:

The anti-HMGB1 mAb effectively ameliorated the clinical skin lesions. The clinical scores in the anti-HMGB1 mAb group were lower than those in the IC mAb group (6.00±0.52 vs. 10.83±0.48, P < 0.001). Histopathologic changes and improvements in the K14-VEGF transgenic homozygous mice were evident after three treatments. The scores of mice in the anti-HMGB1 mAb group were significantly lower than those in the IC mAb group (3.25±0.71 vs. 6.95±0.83, P = 0.0033). The average epidermal thickness in the anti-HMGB1 mAb group was reduced by about 45% when compared with that in the IC mAb group (32.15±7.08 vs. 64.69±7.93, P = 0.0054). Moreover, anti-HMGB1 mAb also decreased the number of infiltrating CD3+ T cells, myeloperoxidase-positive neutrophils, and CD11c+ dendritic cells. The ratio of ear skin γδ T cells was reduced in anti-HMGB1 mAb treated group. The mRNA expression of IL-6, tumor necrosis factor-α, interferon-γ, and IL-17 in the anti-HMGB1 mAb group were significantly reduced when compared with IC mAb group (0.36±0.070 vs.1.98±0.62, P = 0.0148; 6.43±1.37 vs. 13.80±1.33, P = 0.0006; 2.62±0.83 vs. 7.77±1.32, P = 0.0026; 4.69±1.13 vs. 11.41±1.92, P = 0.0054).

Conclusion:

HMGB1 blockade (anti-HMGB1 mAb) reduced leukocyte infiltration and suppressed inflammatory cytokine expression in this K14-VEGF transgenic mouse model, markedly reducing the severity of the psoriasis-like lesions. HMGB1 blockade might serve as a potential target for the treatment of psoriasis.

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贡献者信息

Li-Xin Fu

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Bin Yin

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Na Cao

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Sha Qin

Department of Dermatovenereology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China

Xiao-Yu Lei

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Tao Chen

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Department of Dermatovenereology, Chengdu Qingbaijiang Distinct People’s Hospital, Chengdu, Sichuan 610300, China

Zai-Pei Guo

Department of Dermatovenereology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China

通信作者

Tao Chen

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Department of Dermatovenereology, Chengdu Qingbaijiang Distinct People’s Hospital, Chengdu, Sichuan 610300, China

Email:boyct1217@163.com

Zai-Pei Guo

Department of Dermatovenereology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China

Email:guozp930@163.com

关键词

high-mobility group box 1;inflammatory cytokines;K14-VEGF transgenic mouse;psoriasis

基金项目

The study was supported in part by the Natural Science Foundation of China (No. 81470143)

research grants from the Health and Family Planning Commission of Sichuan Province (Nos. 150005 and 16PJ035)

利益冲突

Conflicts of interest:

The authors reported no conflicts of interest.

历史

出版日期:2023-03-30

收稿日期:2020-10-18

录用日期:2021-07-15

修回日期:2021-01-12

Original Article
HMGB1 Inhibitor Effectively Alleviates Psoriasis-Like Lesions and Inflammatory Cytokines in K14-VEGF Transgenic Mice
Li-Xin Fu,  Bin Yin,  Na Cao,  Sha Qin,  Xiao-Yu Lei,  Tao Chen,  Zai-Pei Guo
Published on 2023-03-30
Cite as Int J Dermatol Venereol, 2023,06(01): 9-14. DOI: 10.1097/JD9.0000000000000209
Abstract
Objective:

Anti-high-mobility group box 1 (HMGB1) is involved in the pathogenesis of many inflammatory and autoimmune diseases, including psoriasis. The present study aimed to investigate the therapeutic effects of HMGB1 monoclonal antibody (mAb) in keratin 14 (K14)-vascular endothelial growth factor (VEGF) transgenic homozygous mice.

Methods:

Twelve VEGF transgenic mice were randomly divided into two groups of six mice each: the anti-HMGB1 mAb group and the immune complex (IC) mAb group. The mice underwent intraperitoneal injection of anti-HMGB1 mAb or IC mAb once every 2 days for a total of three treatments. Compare the lesions on the ears of the mice and evaluate the severity of the lesions using the baseline and clinical scores on the last day of treatment. The changes in psoriasis-like lesions, cellular infiltration of T cells, dendritic cells, and neutrophils were detected by hematoxylin-eosin staining and immunohistochemistry. The mRNA expression of the inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, interferon-γ, and IL-17 in the lesions were assessed by real-time quantitative polymerase chain reaction. The number of γδ T cells in the lesions of two groups were detected by flow cytometry. The t test was used to compare their differences.

Results:

The anti-HMGB1 mAb effectively ameliorated the clinical skin lesions. The clinical scores in the anti-HMGB1 mAb group were lower than those in the IC mAb group (6.00±0.52 vs. 10.83±0.48, P < 0.001). Histopathologic changes and improvements in the K14-VEGF transgenic homozygous mice were evident after three treatments. The scores of mice in the anti-HMGB1 mAb group were significantly lower than those in the IC mAb group (3.25±0.71 vs. 6.95±0.83, P = 0.0033). The average epidermal thickness in the anti-HMGB1 mAb group was reduced by about 45% when compared with that in the IC mAb group (32.15±7.08 vs. 64.69±7.93, P = 0.0054). Moreover, anti-HMGB1 mAb also decreased the number of infiltrating CD3+ T cells, myeloperoxidase-positive neutrophils, and CD11c+ dendritic cells. The ratio of ear skin γδ T cells was reduced in anti-HMGB1 mAb treated group. The mRNA expression of IL-6, tumor necrosis factor-α, interferon-γ, and IL-17 in the anti-HMGB1 mAb group were significantly reduced when compared with IC mAb group (0.36±0.070 vs.1.98±0.62, P = 0.0148; 6.43±1.37 vs. 13.80±1.33, P = 0.0006; 2.62±0.83 vs. 7.77±1.32, P = 0.0026; 4.69±1.13 vs. 11.41±1.92, P = 0.0054).

Conclusion:

HMGB1 blockade (anti-HMGB1 mAb) reduced leukocyte infiltration and suppressed inflammatory cytokine expression in this K14-VEGF transgenic mouse model, markedly reducing the severity of the psoriasis-like lesions. HMGB1 blockade might serve as a potential target for the treatment of psoriasis.

Key words:

high-mobility group box 1; inflammatory cytokines; K14-VEGF transgenic mouse; psoriasis

Contributor Information
Li-Xin Fu

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Bin Yin

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Na Cao

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Sha Qin

Department of Dermatovenereology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China

Xiao-Yu Lei

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Tao Chen

Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China

Department of Dermatovenereology, Chengdu Qingbaijiang Distinct People’s Hospital, Chengdu, Sichuan 610300, China

Zai-Pei Guo

Department of Dermatovenereology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China