Myeloid cell populations and fibrogenic parameters in bleomycin- and HOCl-induced fibrosis.
Mouse models resembling systemic sclerosis can be chemically induced by application of bleomycin or hypochloric acid (HOCl). To date, little is known about inflammatory cells and their potential role in scleroderma (Scl)-related fibrosis. Therefore, we compared both Scl models to define the early immune cell subsets in relation to fibrosis-related parameters. Both agents induced a significant increase in dermal thickness and collagen deposition after 4 weeks, as hallmarks of Scl. However, clinical skin thickness, densely packed, sirius red-stained collagen bundles and collagen cross-links were more pronounced in HOCl-induced Scl. In parallel, there was a significant upregulation of procollagen α1(I), α-SMA and TGF-β transcripts in HOCl animals, whereas IL-1β and MMP-13 mRNA levels were significantly increased in bleomycin-treated mice. Flow cytometric analysis of the Scl skin demonstrated an early cellular infiltrate containing mainly CD19+B cells, CD4+T cells, CD11c+DC and CD11b+myeloid cells, the latter ones being significantly more prominent after HOCl injection. Subanalysis revealed that Scl mice exhibited a significant increase of inflammatory myeloid CD11b+Ly6Clow-highCD64low-highcells (HOCl>bleomycin). In particular, in the HOCl model, activated dermal macrophages (CCR2lowMHCIIhigh) and monocyte-derived DC (CCR2highMHCIIhigh) predominated over less activated CD11b+myeloid cells. In conclusion, the two models differ in certain aspects of the murine and human scleroderma but in the HOCl model, myeloid CD11b+MHCIIhighcells correlate with some fibrosis-related parameters. Therefore, analysis of both models is suggested to cover a comprehensive profile of Scl symptoms but with focus on the HOCl model when the role of early myeloid immune cells will be evaluated.
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. rakerv@uni-mainz.de.|Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. rakerv@uni-mainz.de.
Verena K
VK
Raker
Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Kim Y
KY
Ook
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Jessica
J
Haub
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Nadine
N
Lorenz
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Talkea
T
Schmidt
University Medical Center Münster, Munster, Germany.
Agatha
A
Stegemann
University Medical Center Münster, Munster, Germany.
Markus
M
Böhm
Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Detlef
D
Schuppan
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Kerstin
K
Steinbrink
D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006997:Hypochlorous Acid; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism / Q000473:pathology
D001761:Bleomycin; D006997:Hypochlorous Acid
bleomycin; dermal fibrosis; hypochloric acid; macrophages; myeloid cells