Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin

Monique E Hinchcliff; Diana M. Toledo; Jaclyn N. Taroni; Tammara A. Wood; Jennifer M. Franks; Michael S. Ball; Aileen Hoffmann; Sapna M. Amin; Ainah U. Tan; Kevin Tom; Yolanda Nesbeth; Julia Lee; Madeleine Ma; Kathleen Aren; Mary A. Carns; Patricia A. Pioli; Michael L. Whitfield

doi:10.1016/j.jid.2018.01.006

Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin

Monique E Hinchcliff^*, Diana M. Toledo, Jaclyn N. Taroni, Tammara A. Wood, Jennifer M. Franks, Michael S. Ball, Aileen Hoffmann, Sapna M. Amin, Ainah U. Tan, Kevin Tom, Yolanda Nesbeth, Julia Lee, Madeleine Ma, Kathleen Aren, Mary A. Carns, Patricia A. Pioli, Michael L. Whitfield

^*Corresponding author for this work

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

41 Scopus citations

Abstract

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

Original language	English (US)
Pages (from-to)	1301-1310
Number of pages	10
Journal	Journal of Investigative Dermatology
Volume	138
Issue number	6
DOIs	https://doi.org/10.1016/j.jid.2018.01.006
State	Published - Jun 2018

Funding

This work was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development K12 HD055884 (MH), NIAMS K23 AR059763 (MH), NIAMS R21 AR068035 (MH, MLW), NIAMS P30 AR061920 (MH, MLW), NIAMS R56 AR063985 (PAP), NIAMS R44 AR061920 (MH, YN, MLW), NIGMS T32 GM008704 (JNT), a Cancer Center Support Grant NCI CA060553 and by research awards from the Scleroderma Research Foundation (MH, MLW) and Scleroderma Foundation (PAP). JNT received support from the John H. Copenhaver, Jr. and William H. Thomas, MD 1952 Junior Fellowship from Dartmouth Graduate Studies. MSB received support from The John Osborn Polak Endowment. The Northwestern University Mouse Histology and Phenotyping Laboratory also provided project support. MH and MLW had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors thank the members of the Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility and the Mouse Histology and Phenotyping Laboratory for their assistance with immunohistochemistry. For gene expression inquiries please contact Dr. Whitfield. For clinical inquiries please contact Dr. Hinchcliff. Michael Whitfield is a scientific founder of Celdara LLC, which is developing gene expression biomarkers in SSc. Yolanda Nesbeth is an employee at Celdara Medical LLC. Monique Hinchcliff, Michael Whitfield, and Celdara Medical have received National Institutes of Health Small Business Innovative Research Grant Awards. Monique Hinchcliff and Tammara A. Wood have been paid as consultants, and Michael Whitfield has received distributions from Celdara Medical LLC.

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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Hinchcliff, M. E., Toledo, D. M., Taroni, J. N., Wood, T. A., Franks, J. M., Ball, M. S., Hoffmann, A., Amin, S. M., Tan, A. U., Tom, K., Nesbeth, Y., Lee, J., Ma, M., Aren, K., Carns, M. A., Pioli, P. A., & Whitfield, M. L. (2018). Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin. Journal of Investigative Dermatology, 138(6), 1301-1310. https://doi.org/10.1016/j.jid.2018.01.006

@article{3896e1c41bbb49478fff01b65aabaa48,

title = "Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin",

abstract = "Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.",

author = "Hinchcliff, {Monique E} and Toledo, {Diana M.} and Taroni, {Jaclyn N.} and Wood, {Tammara A.} and Franks, {Jennifer M.} and Ball, {Michael S.} and Aileen Hoffmann and Amin, {Sapna M.} and Tan, {Ainah U.} and Kevin Tom and Yolanda Nesbeth and Julia Lee and Madeleine Ma and Kathleen Aren and Carns, {Mary A.} and Pioli, {Patricia A.} and Whitfield, {Michael L.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = jun,

doi = "10.1016/j.jid.2018.01.006",

language = "English (US)",

volume = "138",

pages = "1301--1310",

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Hinchcliff, ME, Toledo, DM, Taroni, JN, Wood, TA, Franks, JM, Ball, MS, Hoffmann, A, Amin, SM, Tan, AU, Tom, K, Nesbeth, Y, Lee, J, Ma, M, Aren, K, Carns, MA, Pioli, PA & Whitfield, ML 2018, 'Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin', Journal of Investigative Dermatology, vol. 138, no. 6, pp. 1301-1310. https://doi.org/10.1016/j.jid.2018.01.006

TY - JOUR

T1 - Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin

AU - Hinchcliff, Monique E

AU - Toledo, Diana M.

AU - Taroni, Jaclyn N.

AU - Wood, Tammara A.

AU - Franks, Jennifer M.

AU - Ball, Michael S.

AU - Hoffmann, Aileen

AU - Amin, Sapna M.

AU - Tan, Ainah U.

AU - Tom, Kevin

AU - Nesbeth, Yolanda

AU - Lee, Julia

AU - Ma, Madeleine

AU - Aren, Kathleen

AU - Carns, Mary A.

AU - Pioli, Patricia A.

AU - Whitfield, Michael L.

PY - 2018/6

Y1 - 2018/6

N2 - Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

AB - Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

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SN - 0022-202X

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JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

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ER -

Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin

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