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* Tropical Disease Research Unit, University of California, San Francisco, CA 94143;
Institutes of Evolution, Immunology, and Infection Research, University of Edinburgh, Edinburgh, United Kingdom;
Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Institute of Infectious Disease and Molecular Medicine, University of Capetown, South Africa; and
¶ Trudeau Institute, Saranac Lake, NY 12983
Alternatively activated macrophages (AAM
) are found in abundance during chronic Th2 inflammatory responses to metazoan parasites. Important roles for these macrophages are being defined, particularly in the context of Th2-mediated pathology and fibrosis. However, a full understanding of the requirements for alternative activation, particularly at the innate level, is lacking. We present evidence that alternative activation by the Th2 cytokines IL-4 and IL-13 is an innate and rapid response to tissue injury that takes place even in the absence of an infectious agent. This early response does not require CD4+ Th2 cells because it occurred in RAG-deficient mice. However, class II-restricted CD4+ T cell help is essential to maintain AAM in response to infection, because AAM were absent in RAG-deficient and MHC class II-deficient, but not B cell-deficient mice after chronic exposure to the nematode parasite, Brugia malayi. The absence of AAM was associated with increased neutrophilia and reduced eosinophilia, suggesting that AAM are involved in the clearance of neutrophils as well as the recruitment of eosinophils. Consistent with this hypothesis, AAM show enhanced phagocytosis of apoptotic neutrophils, but not latex beads. Our data demonstrate that alternative activation by type 2 cytokines is an innate response to injury that can occur in the absence of an adaptive response. However, analogous to classical activation by microbial pathogens, Th2 cells are required for maintenance and full activation during the ongoing response to metazoan parasites.
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 the Howard Hughes Medical Institute, the Wellcome Trust, and the Medical Research Council (U.K.). P.L. is a recipient of a Wellcome International Research fellowship; M.G.N. is a recipient of a Wellcome Prize fellowship; and I.G. is the recipient of a Wellcome Trust prize PhD studentship.
2 P.L. and I.G. contributed equally to this work.
3 Current address: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104.
4 Address correspondence and reprint requests to Dr. Judith Allen, Institutes of Evolution, Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom. E-mail address: j.allen{at}ed.ac.uk
5 Abbreviations used in this paper: AAM, alternatively activated macrophage; PEC, peritoneal exudate cell; WT, wild type.
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