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Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice.

Madsen M, Hansen PR, Nielsen LB, Hartvigsen K, Pedersen AE, Christensen JP, Aarup A, Pedersen TX - BMC Dermatol. (2016)

Bottom Line: Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively.TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis.The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT

Background: Risk of cardiovascular disease is increased in patients with psoriasis, but molecular mechanisms linking the two conditions have not been clearly established. Lack of appropriate animal models has hampered generation of new knowledge in this area of research and we therefore sought to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation.

Methods: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice.

Results: TPA led to localized skin inflammation with increased epidermal thickness, infiltration of inflammatory-like cells and augmented tissue interleukin-17F levels. Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively. However, atherosclerotic plaque area and composition, and mRNA levels of several inflammatory genes in the aortic wall were not significantly affected by TPA-induced skin inflammation.

Conclusions: TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis. The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

No MeSH data available.


Related in: MedlinePlus

Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) application does not affect atherogenesis in apolipoprotein E deficient (ApoE−/−) mice. Plaque areas measured in control and TPA mice in: a cross sections of the aortic root (μm2), and b the aortic arch en face (% of the aortic arch area); data represent mean values, parametric t-test. In a, the number of sections quantified were n = 4–7/mouse in study 1, and n = 1–4/mouse in study 2. c Quantification of the level of macrophages and monocytes (MOMA-2, brown) and collagen content (Trichrome, blue) in aortic root plaque (depicted as % of the total plaque area in the aortic root, mean values, parametric t-tests). Data from study 1 (n = 5–7/group) are shown as follows: control: unfilled circle; TPA: filled circle, and from study 2 (n = 10–15/group) as control: unfilled triangle; TPA: filled triangle. Also shown representative photos of the two aortic root stainings, with scale bar = 200 μm. d mRNA levels of the macrophage marker F4/80, vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide synthase (iNOS), and monocyte chemoattractant protein 1 (MCP-1) in the aortic arch as measured by real-time quantitative PCR. The expression levels were normalized to the housekeeping gene glycealdehyde-3-phosphate-dehydrogenase (GAPDH). Subsequently, fold expression in TPA mice relative to control mice was calculated and depicted (control mice set to 1 and depicted as a dotted line). Ten mice/group from study 2 were randomly selected for this analysis. Results are shown as median (IQR), and statistical differences were analysed with non-parametric t-test
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Fig3: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) application does not affect atherogenesis in apolipoprotein E deficient (ApoE−/−) mice. Plaque areas measured in control and TPA mice in: a cross sections of the aortic root (μm2), and b the aortic arch en face (% of the aortic arch area); data represent mean values, parametric t-test. In a, the number of sections quantified were n = 4–7/mouse in study 1, and n = 1–4/mouse in study 2. c Quantification of the level of macrophages and monocytes (MOMA-2, brown) and collagen content (Trichrome, blue) in aortic root plaque (depicted as % of the total plaque area in the aortic root, mean values, parametric t-tests). Data from study 1 (n = 5–7/group) are shown as follows: control: unfilled circle; TPA: filled circle, and from study 2 (n = 10–15/group) as control: unfilled triangle; TPA: filled triangle. Also shown representative photos of the two aortic root stainings, with scale bar = 200 μm. d mRNA levels of the macrophage marker F4/80, vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide synthase (iNOS), and monocyte chemoattractant protein 1 (MCP-1) in the aortic arch as measured by real-time quantitative PCR. The expression levels were normalized to the housekeeping gene glycealdehyde-3-phosphate-dehydrogenase (GAPDH). Subsequently, fold expression in TPA mice relative to control mice was calculated and depicted (control mice set to 1 and depicted as a dotted line). Ten mice/group from study 2 were randomly selected for this analysis. Results are shown as median (IQR), and statistical differences were analysed with non-parametric t-test

Mentions: Atherosclerotic plaque area in the aortic root as well as in the aorta en face was similar in TPA-treated and control mice (Figs. 3a and b). Also, we found no differences in plasma cholesterol levels (Additional file 4) or in the composition of the plaques in the aortic root, as assessed by histological staining for macrophages and collagen (Fig. 3c). To investigate whether more subtle inflammatory changes had occurred in the arterial wall, we measured aortic arch mRNA expression of several genes involved in atherogenesis, i.e., macrophage markers (F4/80, murine monocyte chemoattractant protein-1 [MCP-1]), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), and inducible nitric oxide synthase [iNOS]). None of these genes were differentially expressed between TPA and control mice (Fig. 3d).Fig. 3


Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice.

Madsen M, Hansen PR, Nielsen LB, Hartvigsen K, Pedersen AE, Christensen JP, Aarup A, Pedersen TX - BMC Dermatol. (2016)

Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) application does not affect atherogenesis in apolipoprotein E deficient (ApoE−/−) mice. Plaque areas measured in control and TPA mice in: a cross sections of the aortic root (μm2), and b the aortic arch en face (% of the aortic arch area); data represent mean values, parametric t-test. In a, the number of sections quantified were n = 4–7/mouse in study 1, and n = 1–4/mouse in study 2. c Quantification of the level of macrophages and monocytes (MOMA-2, brown) and collagen content (Trichrome, blue) in aortic root plaque (depicted as % of the total plaque area in the aortic root, mean values, parametric t-tests). Data from study 1 (n = 5–7/group) are shown as follows: control: unfilled circle; TPA: filled circle, and from study 2 (n = 10–15/group) as control: unfilled triangle; TPA: filled triangle. Also shown representative photos of the two aortic root stainings, with scale bar = 200 μm. d mRNA levels of the macrophage marker F4/80, vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide synthase (iNOS), and monocyte chemoattractant protein 1 (MCP-1) in the aortic arch as measured by real-time quantitative PCR. The expression levels were normalized to the housekeeping gene glycealdehyde-3-phosphate-dehydrogenase (GAPDH). Subsequently, fold expression in TPA mice relative to control mice was calculated and depicted (control mice set to 1 and depicted as a dotted line). Ten mice/group from study 2 were randomly selected for this analysis. Results are shown as median (IQR), and statistical differences were analysed with non-parametric t-test
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Related In: Results  -  Collection

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Fig3: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) application does not affect atherogenesis in apolipoprotein E deficient (ApoE−/−) mice. Plaque areas measured in control and TPA mice in: a cross sections of the aortic root (μm2), and b the aortic arch en face (% of the aortic arch area); data represent mean values, parametric t-test. In a, the number of sections quantified were n = 4–7/mouse in study 1, and n = 1–4/mouse in study 2. c Quantification of the level of macrophages and monocytes (MOMA-2, brown) and collagen content (Trichrome, blue) in aortic root plaque (depicted as % of the total plaque area in the aortic root, mean values, parametric t-tests). Data from study 1 (n = 5–7/group) are shown as follows: control: unfilled circle; TPA: filled circle, and from study 2 (n = 10–15/group) as control: unfilled triangle; TPA: filled triangle. Also shown representative photos of the two aortic root stainings, with scale bar = 200 μm. d mRNA levels of the macrophage marker F4/80, vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide synthase (iNOS), and monocyte chemoattractant protein 1 (MCP-1) in the aortic arch as measured by real-time quantitative PCR. The expression levels were normalized to the housekeeping gene glycealdehyde-3-phosphate-dehydrogenase (GAPDH). Subsequently, fold expression in TPA mice relative to control mice was calculated and depicted (control mice set to 1 and depicted as a dotted line). Ten mice/group from study 2 were randomly selected for this analysis. Results are shown as median (IQR), and statistical differences were analysed with non-parametric t-test
Mentions: Atherosclerotic plaque area in the aortic root as well as in the aorta en face was similar in TPA-treated and control mice (Figs. 3a and b). Also, we found no differences in plasma cholesterol levels (Additional file 4) or in the composition of the plaques in the aortic root, as assessed by histological staining for macrophages and collagen (Fig. 3c). To investigate whether more subtle inflammatory changes had occurred in the arterial wall, we measured aortic arch mRNA expression of several genes involved in atherogenesis, i.e., macrophage markers (F4/80, murine monocyte chemoattractant protein-1 [MCP-1]), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), and inducible nitric oxide synthase [iNOS]). None of these genes were differentially expressed between TPA and control mice (Fig. 3d).Fig. 3

Bottom Line: Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively.TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis.The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT

Background: Risk of cardiovascular disease is increased in patients with psoriasis, but molecular mechanisms linking the two conditions have not been clearly established. Lack of appropriate animal models has hampered generation of new knowledge in this area of research and we therefore sought to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation.

Methods: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice.

Results: TPA led to localized skin inflammation with increased epidermal thickness, infiltration of inflammatory-like cells and augmented tissue interleukin-17F levels. Systemic effects of the topical application of TPA were demonstrated by increased plasma concentration of serum amyloid A and splenic immune modulation, respectively. However, atherosclerotic plaque area and composition, and mRNA levels of several inflammatory genes in the aortic wall were not significantly affected by TPA-induced skin inflammation.

Conclusions: TPA-induced psoriasis-like skin inflammation in atherosclerosis-prone ApoE(-/-) mice evoked systemic immune-inflammatory effects, but did not affect atherogenesis. The results may question the role of psoriasis-induced inflammation in the pathogenesis of atherosclerosis in psoriasis patients.

No MeSH data available.


Related in: MedlinePlus