ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model

Amy M. Archer; Rana Saber; Shawn Rose; Alexander Shaffer; Alexander V. Misharin; Fu Nien Tsai; G. Kenneth Haines; Salina Dominguez; Mesut Eren; Douglas E. Vaughan; Carla M. Cuda; Harris Perlman

doi:10.1186/s12967-016-0912-y

ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model

Amy M. Archer, Rana Saber, Shawn Rose, Alexander Shaffer, Alexander V. Misharin, Fu Nien Tsai, G. Kenneth Haines, Salina Dominguez, Mesut Eren, Douglas E. Vaughan, Carla M. Cuda^*, Harris Perlman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Background: The risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. While patients with RA also have dyslipidemia, the impact of dyslipidemia on the severity of inflammatory arthritis and associated cardiovascular disease is unclear. Currently, there are conflicting results regarding arthritis incidence in apolipoprotein E (ApoE) deficient mice, which spontaneously exhibit both hyperlipidemia and atherosclerosis. Here, we utilize a distinct approach to investigate the contribution of a hyperlipidemic environment on the development of arthritis and atherosclerosis in mice lacking ApoE. Methods: K/BxN serum transfer-induced arthritis (STIA) was assessed in C57BL/6 (control) and ApoE^-/- mice using clinical indices and immunohistochemical staining. Ankle synoviums were processed for flow cytometry. Aortic atherosclerosis was quantitated using Sudan IV staining. Serum cholesterol and cytokine levels were determined via enzymatic and luminex bead-based assays, respectively. Results: ApoE^-/- mice developed a sustained and enhanced semi-chronic inflammatory arthritis as compared to control mice. ApoE^-/- mice had increased numbers of foamy macrophages, enhanced joint inflammation and amplified collagen deposition versus controls. The presence of arthritis did not exacerbate serum cholesterol levels or significantly augment the level of atherosclerosis in ApoE^-/- mice. However, arthritic ApoE^-/- mice exhibited a marked elevation of IL-6 as compared to non-arthritic ApoE^-/- mice and arthritic C57BL/6 mice. Conclusions: Loss of ApoE potentiates a semi-chronic inflammatory arthritis. This heightened inflammatory response was associated with an increase in circulating IL-6 and in the number of foamy macrophages within the joint. Moreover, the foamy macrophages within the arthritic joint are reminiscent of those within unstable atherosclerotic lesions and suggest a pathologic role for foamy macrophages in propagating arthritis.

Original language	English (US)
Article number	170
Journal	Journal of Translational Medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s12967-016-0912-y
State	Published - Jun 10 2016

Funding

This work was supported by NIH Grant AR007611, NIH Loan Repayment Grant, and the American College of Rheumatology Research and Education Foundation to SR, Driskill Fellowship and NIH T32 AR007611 to AMA, American Heart Association Grant PRE21410010 to FT, NIH Grants HL051387 and HL108795 to DEV, NIH grant K01AR064313 to CMC, and NIH Grants (AR064546-01, AR050250, AR054796, AI092490 and HL108795) and Funds provided by the Solovy-Arthritis Research Society Chair in Medicine to HP. The authors would like to thank Jungwa Lee within the Division of Preventative Medicine at Northwestern University for advice on statistical analysis, Sheila Murphy for technical support and Katherine Barnes for technical support.

Keywords

Animal models of human disease
Arthritis
Cholesterol
Inflammation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12967-016-0912-y

Cite this

Archer, A. M., Saber, R., Rose, S., Shaffer, A., Misharin, A. V., Tsai, F. N., Haines, G. K., Dominguez, S., Eren, M., Vaughan, D. E., Cuda, C. M., & Perlman, H. (2016). ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model. Journal of Translational Medicine, 14(1), Article 170. https://doi.org/10.1186/s12967-016-0912-y

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title = "ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model",

abstract = "Background: The risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. While patients with RA also have dyslipidemia, the impact of dyslipidemia on the severity of inflammatory arthritis and associated cardiovascular disease is unclear. Currently, there are conflicting results regarding arthritis incidence in apolipoprotein E (ApoE) deficient mice, which spontaneously exhibit both hyperlipidemia and atherosclerosis. Here, we utilize a distinct approach to investigate the contribution of a hyperlipidemic environment on the development of arthritis and atherosclerosis in mice lacking ApoE. Methods: K/BxN serum transfer-induced arthritis (STIA) was assessed in C57BL/6 (control) and ApoE-/- mice using clinical indices and immunohistochemical staining. Ankle synoviums were processed for flow cytometry. Aortic atherosclerosis was quantitated using Sudan IV staining. Serum cholesterol and cytokine levels were determined via enzymatic and luminex bead-based assays, respectively. Results: ApoE-/- mice developed a sustained and enhanced semi-chronic inflammatory arthritis as compared to control mice. ApoE-/- mice had increased numbers of foamy macrophages, enhanced joint inflammation and amplified collagen deposition versus controls. The presence of arthritis did not exacerbate serum cholesterol levels or significantly augment the level of atherosclerosis in ApoE-/- mice. However, arthritic ApoE-/- mice exhibited a marked elevation of IL-6 as compared to non-arthritic ApoE-/- mice and arthritic C57BL/6 mice. Conclusions: Loss of ApoE potentiates a semi-chronic inflammatory arthritis. This heightened inflammatory response was associated with an increase in circulating IL-6 and in the number of foamy macrophages within the joint. Moreover, the foamy macrophages within the arthritic joint are reminiscent of those within unstable atherosclerotic lesions and suggest a pathologic role for foamy macrophages in propagating arthritis.",

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author = "Archer, {Amy M.} and Rana Saber and Shawn Rose and Alexander Shaffer and Misharin, {Alexander V.} and Tsai, {Fu Nien} and Haines, {G. Kenneth} and Salina Dominguez and Mesut Eren and Vaughan, {Douglas E.} and Cuda, {Carla M.} and Harris Perlman",

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doi = "10.1186/s12967-016-0912-y",

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T1 - ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model

AU - Archer, Amy M.

AU - Saber, Rana

AU - Rose, Shawn

AU - Shaffer, Alexander

AU - Misharin, Alexander V.

AU - Tsai, Fu Nien

AU - Haines, G. Kenneth

AU - Dominguez, Salina

AU - Eren, Mesut

AU - Vaughan, Douglas E.

AU - Cuda, Carla M.

AU - Perlman, Harris

PY - 2016/6/10

Y1 - 2016/6/10

N2 - Background: The risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. While patients with RA also have dyslipidemia, the impact of dyslipidemia on the severity of inflammatory arthritis and associated cardiovascular disease is unclear. Currently, there are conflicting results regarding arthritis incidence in apolipoprotein E (ApoE) deficient mice, which spontaneously exhibit both hyperlipidemia and atherosclerosis. Here, we utilize a distinct approach to investigate the contribution of a hyperlipidemic environment on the development of arthritis and atherosclerosis in mice lacking ApoE. Methods: K/BxN serum transfer-induced arthritis (STIA) was assessed in C57BL/6 (control) and ApoE-/- mice using clinical indices and immunohistochemical staining. Ankle synoviums were processed for flow cytometry. Aortic atherosclerosis was quantitated using Sudan IV staining. Serum cholesterol and cytokine levels were determined via enzymatic and luminex bead-based assays, respectively. Results: ApoE-/- mice developed a sustained and enhanced semi-chronic inflammatory arthritis as compared to control mice. ApoE-/- mice had increased numbers of foamy macrophages, enhanced joint inflammation and amplified collagen deposition versus controls. The presence of arthritis did not exacerbate serum cholesterol levels or significantly augment the level of atherosclerosis in ApoE-/- mice. However, arthritic ApoE-/- mice exhibited a marked elevation of IL-6 as compared to non-arthritic ApoE-/- mice and arthritic C57BL/6 mice. Conclusions: Loss of ApoE potentiates a semi-chronic inflammatory arthritis. This heightened inflammatory response was associated with an increase in circulating IL-6 and in the number of foamy macrophages within the joint. Moreover, the foamy macrophages within the arthritic joint are reminiscent of those within unstable atherosclerotic lesions and suggest a pathologic role for foamy macrophages in propagating arthritis.

AB - Background: The risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. While patients with RA also have dyslipidemia, the impact of dyslipidemia on the severity of inflammatory arthritis and associated cardiovascular disease is unclear. Currently, there are conflicting results regarding arthritis incidence in apolipoprotein E (ApoE) deficient mice, which spontaneously exhibit both hyperlipidemia and atherosclerosis. Here, we utilize a distinct approach to investigate the contribution of a hyperlipidemic environment on the development of arthritis and atherosclerosis in mice lacking ApoE. Methods: K/BxN serum transfer-induced arthritis (STIA) was assessed in C57BL/6 (control) and ApoE-/- mice using clinical indices and immunohistochemical staining. Ankle synoviums were processed for flow cytometry. Aortic atherosclerosis was quantitated using Sudan IV staining. Serum cholesterol and cytokine levels were determined via enzymatic and luminex bead-based assays, respectively. Results: ApoE-/- mice developed a sustained and enhanced semi-chronic inflammatory arthritis as compared to control mice. ApoE-/- mice had increased numbers of foamy macrophages, enhanced joint inflammation and amplified collagen deposition versus controls. The presence of arthritis did not exacerbate serum cholesterol levels or significantly augment the level of atherosclerosis in ApoE-/- mice. However, arthritic ApoE-/- mice exhibited a marked elevation of IL-6 as compared to non-arthritic ApoE-/- mice and arthritic C57BL/6 mice. Conclusions: Loss of ApoE potentiates a semi-chronic inflammatory arthritis. This heightened inflammatory response was associated with an increase in circulating IL-6 and in the number of foamy macrophages within the joint. Moreover, the foamy macrophages within the arthritic joint are reminiscent of those within unstable atherosclerotic lesions and suggest a pathologic role for foamy macrophages in propagating arthritis.

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KW - Cholesterol

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ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model

Abstract

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UN SDGs

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