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CD11b⁺ Monocytes Abrogate Th17 CD4⁺ T Cell-Mediated Experimental Autoimmune Myocarditis¹

Alan Valaperti^*, René R. Marty^*, Gabriela Kania^*, Davide Germano^*, Nora Mauermann^*, Stefan Dirnhofer, Bernd Leimenstoll, Przemyslaw Blyszczuk^*, Chen Dong, Christian Mueller, Lukas Hunziker^*, and Urs Eriksson^2,*,

^* Experimental Critical Care Medicine, Department of Research, University Hospital, Basel, Switzerland; Department of Pathology, University Hospital, Basel, Switzerland; Department of Internal Medicine, University Hospital, Basel, Switzerland; and Department of Immunology, M. D. Anderson Cancer Center, Houston, TX 77030

Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after -myosin H chain peptide (MyHC-)/CFA immunization and largely resolving thereafter. In IFN-R^–/– mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-R^–/– mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b⁺ monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b⁺ monocytes suppressed MyHC--specific Th17 T cell responses IFN--dependently in vitro. In vivo, injection of IFN-R^+/+CD11b⁺, but not IFN-R^–/–CD11b⁺, monocytes, suppressed MyHC--specific T cells, and abrogated the progressive disease course in IFN-R^–/– mice. Finally, coinjection of MyHC--specific, but not OVA-transgenic, IFN--releasing CD4⁺ Th1 T cell lines, together with MyHC--specific Th17 T cells protected RAG2^–/– mice from EAM. In conclusion, CD11b⁺ monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN--dependent negative feedback loop confining disease progression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Astra Zeneca; Menarini; the Board of the Chief Physicians of the Internal Medicine Department of Basel University Hospital; the Gebert Rüf Foundation; and the Swiss National Foundation. U.E. holds a Swiss National Foundation Professorship in Internal and Critical Care Medicine.

² Address correspondence and reprint requests to Dr. Urs Eriksson, Department of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail address: ueriksson{at}uhbs.ch

³ Abbreviations used in this paper: DCM, dilated cardiomyopathy; EAM, experimental autoimmune myocarditis; MyHC-, -myosin H chain peptide; NOS, nitric oxide synthetase; L-NAME, N-nitro-L-arginine-methyl-ester; SDF, stromal cell-derived factor.

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