Macrophage activation comprises a continuum of functional states critically determined by cytokine microenvironment. Activated macrophages have been functionally grouped according to their response to pro-Th1/proinflammatory stimuli [lipopolysaccharide, IFNγ, granulocyte macrophage colony-stimulating factor (GM-CSF); M1] or pro-Th2/antiinflammatory stimuli [interleukin (IL)-4, IL-10, M-CSF; M2]. We report that folate receptor β (FRβ), encoded by the FOLR2 gene, is a marker for macrophages generated in the presence of M-CSF (M2), but not GM-CSF (M1), and whose expression correlates with increased folate uptake ability. The acquisition of folate uptake ability by macrophages is promoted by M-CSF, maintained by IL-4, prevented by GM-CSF, and reduced by IFNγ, indicating a link between FRβ expression and M2 polarization. In agreement with in vitro data, FRβ expression is detected in tumor-associated macrophages (TAM), which exhibit an M2-like functional profile and exert potent immunosuppressive functions within the tumor environment. FRβ is expressed, and mediates folate uptake, by CD163 + CD68 + CD14 + IL-10-producing TAM, and its expression is induced by tumorderived ascitic fluid and conditioned medium from fibroblasts and tumor cell lines in an M-CSF-dependent manner. These results establish FRβ as a marker for M2 regulatory macrophage polarization and indicate that folate conjugates of therapeutic drugs are a potential immunotherapy tool to target TAM. [Cancer Res 2009;69(24):9395-403]

Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT1–7) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization–associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT7 mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT2B and 5HT7 receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT2B was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT2B and 5HT7, whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.

Dendritic cell-specific ICAM-3–grabbing nonintegrin (DC-SIGN; CD209) is a human pathogen-attachment C-type lectin with no obvious murine ortholog and for which ligation leads to enhanced anti-inflammatory cytokine release and altered proinflammatory cytokine production. Although induced by IL-4 in monocytes and considered as a DC marker, DC-SIGN expression on human APCs under homeostatic conditions is so far unexplained. We report in this study that M-CSF enhances DC-SIGN expression on in vitro derived anti-inflammatory macrophages and that M-CSF mediates the induction of DC-SIGN by fibroblast- and tumor cell-conditioned media. The M-CSF–inducible DC-SIGN expression along monocyte-to-macrophage differentiation is dependent on JNK and STAT3 activation, potentiated by STAT3-activating cytokines (IL-6, IL-10), and abrogated by the M1-polarizing cytokine GM-CSF. In pathological settings, DC-SIGN expression is detected in tumor tissues and on ex vivo-isolated CD14+ CD163+ IL-10–producing tumor-associated macrophages. Importantly, DC-SIGN Abs reduced the release of IL-10 from macrophages exposed to Lewisx-expressing SKBR3 tumor cells. These results indicate that DC-SIGN is expressed on both wound-healing (IL-4–dependent) and regulatory (M-CSF–dependent) alternative (M2) macrophages and that DC-SIGN expression on tumor-associated macrophages might help tumor progression by contributing to the maintenance of an immunosuppressive environment.

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Allergens Ani s 1 and Ani s 4 have demonstrated their utility for the diagnosis of the sensitization to larvae of the genus Anisakis. The aim was to determine the number of patients with compatible clinical history, who did not recognize Ani s 1 and Ani s 4, and characterize the allergens responsible for their sensitization. Eighty-four patients were studied by CAP and immunoglobulin E (IgE) immunoblotting. The 12% of the patients recognized allergens different from Ani s 1 and Ani s 4, being half sensitized to a heat-resistant 15-kDa allergen, which was isolated by ethanol fractionation, followed by a hydroxyapatite chromatography and a reversed-phase high-performance liquid chromatography and identified by its amino terminal sequence as Ani s 5. A total of 41 of the 84 patients studied (49%) showed specific IgE to Ani s 5 that was detected among the excretory-secretory products and immunohistochemically located at the excretory gland, ventriculus, and the luminal surface of the intestinal epithelium of the larvae.

Dermatophilus congolensis, which affects animal species, is an uncommon human infection. Few cases, mainly in tropical areas, have been reported. We describe the first human infection in Spain in a traveler returning from Central America. Diagnosis of human infection may be underestimated in people in contact with animals. CASE REPORTIn September 2009, a 26-year-old woman came to the Tropical Diseases Service, Hospital Carlos III, Madrid, Spain, with skin lesions on her right wrist and no other symptoms. Two months prior to her presentation, the patient spent 15 days in Costa Rica working as a volunteer on a dairy farm. She reported close contact with animals, including feeding and milking cows, as well as drinking raw milk. She did not report any other contact with livestock in Spain, either professionally or in leisure activities. The patient had been vaccinated against diphtheria and tetanus in 2003. In addition, she was vaccinated against hepatitis B (third dose), hepatitis A (first dose), typhoid fever, and rabies 2 weeks before her trip. She followed a correct malaria prophylaxis with chloroquine. No other previous medical history was of interest. Five days after her arrival in Costa Rica, she noticed a vesicular eruption over a scratched area on her right wrist that evolved to pustules and crust 4 days later. The eruption relapsed on several occasions and was painful and itchy. Neither fever nor lymph node swelling was present. She had begun self-treatment with topical gentamicin and corticosteroid ointment 1 month before medical consultation, with a mild improvement. The patient's physical examination revealed five erythematous, desquamative lesions of less than 0.5 cm in diameter and with elevated edges. Topical treatment was discontinued, and a sample for microbiological analysis was taken. One month later, the lesions had disappeared.Swab samples were taken from the lesions and sent to our laboratory for bacterial and fungal culture analyses. They were directly inoculated in blood and chocolate agar, thioglycolate broth, Sabouraud chloramphenicol, and Sabouraud cycloheximide (Actidione)-chloramphenicol agar. Blood and chocolate agar and thioglycolate broth were incubated at 35°C in an aerobic atmosphere, the chocolate agar was incubated in air supplemented with 5% CO 2 , and the blood agar was also incubated in an anaerobic atmosphere. Sabouraud chloramphenicol and Sabouraud cycloheximide-chloramphenicol agar plates were incubated at 32°C. After 24 h, a pure culture of tiny, point-like, smooth, creamy white-colored, beta-hemolytic colonies adherent to the media grew in aerobic blood agar and chocolate agar. Gram staining showed hypha-like, branching filaments with "train track" form and clusters of sporangia as well as coccoid Gram-positive forms, mostly in chains (Fig. 1). After 48 h, crowded colonies became yellowish and mucoid, with a great variation in colonial morphology, e.g., pulvinate, umbonate, or cake crumb-like (Fig. 2). At that time, released sporangia were the main finding in the Gram sta...