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Previous work has demonstrated that a subset of macrophages expresses a folate receptor (FR) that can mediate internalization of folate-linked molecules, including imaging and therapeutic agents. To characterize this subset, macrophages were collected from peritoneal cavities of mice injected with saline, thioglycolate, zymosan, heat-killed or live bacteria, and cell-surface markers that coexpress with FR were identified. Virtually no F4/80 ؉ peritoneal macrophages from salineinjected mice expressed FR, whereas numerous macrophages from mice injected with each inflammatory stimulus expressed FR. Examination of cell differentiation antigens that are up-regulated in FR ؉ macrophages revealed markers characteristic of an activated state (CD80, CD86, Ly-6C/G), whereas macrophages lacking these activation markers expressed few or no FR. FR ؉ macrophages also produced tumor necrosis factor-␣ (TNF-␣) and reactive oxygen species, and production of reactive oxygen species correlated linearly with expression of FR. Synovial macrophages collected from arthritic patients were found to bind and internalize folate-linked dyes. Moreover, a folate-linked radioimaging agent was shown to image inflamed joints of rheumatoid arthritic patients. These results suggest that FR constitutes a marker for macrophage activation and that FR ؉ macrophages can be targeted with folatelinked drugs without promoting drug uptake by nonactivated macrophages. This trial was registered at www. clinicaltrials.gov as #NCT00588393. IntroductionIn the absence of inflammatory signals, tissue-resident macrophages participate primarily in tissue homeostasis. [1][2][3][4] However, when induced with inflammatory stimuli, macrophages become activated and mobilize disease-resistance mechanisms by releasing proinflammatory mediators that both activate defense responses in adjacent cells and recruit immune cells to sites of inflammation. [1][2][3][4] In most tissues, activated macrophages can be easily distinguished from their tissue-resident counterparts by both the molecules they secrete (eg, cytokines) and the cell-surface antigens they express (eg, CD80 [B7.1], CD86 [B7.2], Ly6C/G [Gr-1]). [5][6][7] Although activated macrophages primarily serve to protect against opportunistic infections, 7,8 when they become activated inappropriately, they can participate in the development of autoimmune and inflammatory diseases. Thus, activated macrophages have been shown to play an integral role in the etiology of diseases, such as rheumatoid arthritis, 9,10 lupus, 11,12 , digestive enzymes (eg, collagenases), prostaglandins, and reactive oxygen species (ROS), which can aggravate or accelerate damage to the normal tissues. 1,9,21 In earlier studies of rheumatoid arthritis, inflamed joints were observed to accumulate a subpopulation of macrophages that also express a receptor for the vitamin, folic acid. 24 Because no other tissues/cell types except the kidneys and certain malignant cells expressed this folate receptor (FR), accumulation of FR ϩ macrophages in arthr...

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Activated macrophages are commonly involved in the pathogenesis of inflammatory and autoimmune diseases and have been frequently reported to overexpress FR-β. Although FR-targeted therapies aimed at eliminating activated macrophages have shown promise for treating inflammatory diseases, little work has been performed to evaluate whether other hematopoietic cells might also express FR-β. Analysis of peripheral blood cells with a mAb to human FR-β reveals that only monocytes express FR-β. Molecular characterization of these circulating monocytes further demonstrates that solely the classic/proinflammatory subset (CD14(high)CD16(-)) expresses the FR and that only CD14(high)CD16(-) FR-β(+) monocytes also display the ability to bind folate-linked molecules. Confirmation that this subset of monocytes indeed constitutes the proinflammatory subpopulation was obtained by demonstrating coexpression of FR-β with other proinflammatory markers, including CCR2 and HLA-DR. Synovial monocytes from the joints of patients with RA were also shown to express FR-β. As inhibition of the chemotaxis of proinflammatory monocytes into sites of inflammation has been explored frequently as a means of controlling autoimmune diseases, demonstration that FR-β is uniquely expressed on this proinflammatory subpopulation offers a new strategy to suppress migration of inflammatory monocytes into sites of inflammation.

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