Study on the therapeutic effect of andrographolide on psoriasis mouse model by regulating cGAS-STING signal pathway

doi:10.11958/20230914

Abstract

Abstract:

Objective To explore the therapeutic mechanism of andrographolide (Andro) on psoriasis mice by regulating GMP-AMP synthase-stimulator of interferon genes signal pathway (cGAS STING signal pathway). Methods Ninety BALB/c mice were divided into the control group, the model group, the Andro low dose group, the Andro medium dose group, the Andro high dose groups (Andro-L, M, H groups, 10, 30 and 50 mg•kg^-1•d^-1Andro) and the high dose Andro+STING activator DMXAA group (Andro-H+DMXAA group, 50 mg•kg^-1•d^-1 Andro+5 mg•kg^-1•d^-1 DMXAA). Except for the control group, mice of the other groups were administered imiquimod (IMQ) on back to establish the psoriasis mouse model. The psoriasis area of mice was observed, and severity index (PASI) scoring was performed. Serum levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-23, IL-17A, interferon (IFN)-γ and IFN-β were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin eosin (HE) staining and toluidine blue staining were used to detect the epidermal thickness and mast cell count. Immunofluorescence staining was applied to detect the expression rates of Ki-67 and CD4 positive cells. RT-qPCR was applied to detect the expression level of cGAS and STING mRNA, and Western blot assay was applied to detect levels of cGAS, STING, interferon regulatory factor-3 (IRF3) and p-IRF3 proteins. Results Compared with the control group, the back skin of mice in the model group showed severe erythema, scales and a large number of inflammatory cell infiltration. The scratch times, PASI score, epidermal thickness, number of mast cells, levels of IL-6, IL-1β, TNF-α, IL-23, IL-17A, IFN-γ and IFN-β, the expression rates of Ki-67 and CD4 positive cell, the expression level of cGAS and STING mRNA and protein, and IRF3 phosphorylation level were increased obviously (P<0.05). Compared with the model group, skin erythema, scales and inflammatory cell infiltration were reduced in the Andro-L, Andro-M and Andro-H groups. The scratch times, PASI score, epidermal thickness, number of mast cells, levels of IL-6, IL-1β, TNF-α, IL-23, IL-17A, IFN-γ and IFN-β, the expression rates of Ki-67 and CD4 positive cells, the expression levels of cGAS and STING mRNA and protein, and IRF3 phosphorylation level were decreased in a dose-dependent manner (P<0.05). STING activator DMXAA reversed the protective effect of Andro on psoriasis mice (P<0.05). Conclusion Andrographolide can improve psoriasis symptoms in mice by inhibiting the cGAS-STING signaling pathway.

Key words: Andrographolide, psoriasis, inflammation, GMP-AMP synthase-stimulator of interferon genes signaling pathway

CLC Number:

R758.63

Figures/Tables 12

References 27

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组别	抓挠次数/次	PASI评分/分
Control组	5.16±0.61	0
Model组	29.43±4.06^a	2.93±0.46
Andro-L组	23.74±3.81^b	2.47±0.50^b
Andro-M组	16.52±2.04^bc	1.93±0.26^bc
Andro-H组	10.76±1.61^bcd	0.73±0.46^bcd
Andro-H+DMXAA组	13.42±1.74^e	1.40±0.50^e
F	170.859^＊＊	56.872^＊＊

组别	抓挠次数/次	PASI评分/分
Control组	5.16±0.61	0
Model组	29.43±4.06^a	2.93±0.46
Andro-L组	23.74±3.81^b	2.47±0.50^b
Andro-M组	16.52±2.04^bc	1.93±0.26^bc
Andro-H组	10.76±1.61^bcd	0.73±0.46^bcd
Andro-H+DMXAA组	13.42±1.74^e	1.40±0.50^e
F	170.859^＊＊	56.872^＊＊

组别	IL-6	IL-1β	TNF-α	IL-23	IL-17A
Control组	86.36±7.03	54.16±6.89	80.43±8.16	33.86±3.05	152.23±16.08
Model组	159.76±12.46^a	117.24±12.03^a	246.48±21.31^a	101.62±9.11^a	326.06±28.57^a
Andro-L组	143.86±10.35^b	103.66±7.43^b	183.35±16.25^b	87.38±7.12^b	275.24±24.46^b
Andro-M组	127.71±9.82^bc	94.26±8.51^bc	129.52±11.07^bc	62.10±6.08^bc	244.18±20.31^bc
Andro-H组	103.52±9.21^bcd	72.31±6.56^bcd	98.34±9.76^bcd	43.91±5.07^bcd	187.09±19.17^bcd
Andro-H+DMXAA组	115.38±10.94^e	83.19±8.01^e	113.71±10.92^e	51.24±5.10^e	208.85±19.22^e
F	105.412^＊＊	107.583^＊＊	309.341^＊＊	267.107^＊＊	126.150^＊＊

组别	IL-6	IL-1β	TNF-α	IL-23	IL-17A
Control组	86.36±7.03	54.16±6.89	80.43±8.16	33.86±3.05	152.23±16.08
Model组	159.76±12.46^a	117.24±12.03^a	246.48±21.31^a	101.62±9.11^a	326.06±28.57^a
Andro-L组	143.86±10.35^b	103.66±7.43^b	183.35±16.25^b	87.38±7.12^b	275.24±24.46^b
Andro-M组	127.71±9.82^bc	94.26±8.51^bc	129.52±11.07^bc	62.10±6.08^bc	244.18±20.31^bc
Andro-H组	103.52±9.21^bcd	72.31±6.56^bcd	98.34±9.76^bcd	43.91±5.07^bcd	187.09±19.17^bcd
Andro-H+DMXAA组	115.38±10.94^e	83.19±8.01^e	113.71±10.92^e	51.24±5.10^e	208.85±19.22^e
F	105.412^＊＊	107.583^＊＊	309.341^＊＊	267.107^＊＊	126.150^＊＊

组别	IFN-γ	IFN-β
Control组	50.43±6.07	16.46±1.53
Model组	174.58±18.03^a	89.14±9.76^a
Andro-L组	137.16±13.54^b	64.53±6.01^b
Andro-M组	102.15±9.43^bc	43.68±4.96^bc
Andro-H组	67.28±7.11^bcd	23.72±2.11^bcd
Andro-H+DMXAA组	83.49±7.07^e	34.68±2.94^e
F	262.388^＊＊	389.008^＊＊