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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901473v1 183/10/6733    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Lin, S. L. Articles by Duffield, J. S. PubMed PubMed Citation Articles by Lin, S. L. Articles by Duffield, J. S.

Bone Marrow Ly6C^high Monocytes Are Selectively Recruited to Injured Kidney and Differentiate into Functionally Distinct Populations¹

Shuei Liong Lin,^* Ana P. Castaño,^* Brian T. Nowlin,^* Mark L. Lupher, Jr., and Jeremy S. Duffield^2*

^*Laboratory of Inflammation Research, Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Promedior Inc., Malvern, PA 19355; and Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

Roles for monocyte/macrophages (M) in directing the development of tissue fibrosis are increasingly recognized. Macrophages form a heterogeneous group of inflammatory leukocytes, and the mechanisms by which they acquire heterogeneity and its functional significance are unclear. We used the unilateral ureteral obstruction model of progressive kidney fibrosis to explore macrophage heterogeneity and function further. Unilateral ureteral obstruction kidney Ms form three distinct subpopulations defined by the marker Ly6C, all of which are derived from a single Ly6C^high bone marrow monocyte population selectively recruited to the kidney. Conditional ablation of these Ms in vivo in CD11b-DTR mice is potently antifibrotic. The mRNA transcription profile of these populations is consistent with differential functional roles for each subpopulation, with Ly6C^low macrophages transcribing genes consistent with selective profibrotic or M2-type function. Furthermore, bone marrow chimerism studies indicate that although resident kidney macrophages proliferate markedly to comprise up to 40% of the inflammatory macrophage population, they do not contribute to fibrosis. Our data identify Ly6C as a marker of functionally discrete tissue macrophage subsets and support a model of selective recruitment of Ly6C^high bone marrow monocytes to the kidney that differentiate into three populations of kidney macrophages, including a profibrotic Ly6C^low population.

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 National Institutes of Health Grants DK73299 and DK084077, the Genzyme Renal Innovations Program, the American Society of Nephrology Gottschalk Award, Promedior Inc. (all to J.S.D.), and National Science Council Awards 095-2314-B-002-310 and 095-SAF-I-564-601-TMS (to S.L.L.). These studies were presented in part at the 41st Annual Meeting of the American Society of Nephrology in Philadelphia, PA, November 4–9, 2008 and at the 96th Annual Meeting of the American Association of Immunologists Meeting in Seattle, WA, May 8–12, 2009.

² Address correspondence and reprint requests to Dr. Jeremy Duffield, Laboratory of Inflammation Research, Brigham and Women’s Hospital. Harvard Institute of Medicine, Room 574, 4 Blackfan Circle, Boston, MA 02115. E-mail address: jduffield{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: M, macrophage; BM, bone marrow; DAPI, 4',6-diamidino-2-phenylindole; DC, dendritic cell; DT, diphtheria toxin; DTR, DT receptor; FSC, forward scatter; int, intermediate; PBM, peripheral blood monocyte; SSC, side scatter; UUO, unilateral ureteric obstruction; WT, wild type.

⁴ The online version of this article contains supplemental material.