Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Abstract

Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ⌬dblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ⌬dblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis. Cryptococcus neoformans is a facultative intracellular pathogen that is acquired by inhalation of spores and/or desiccated yeasts and leads to latent pulmonary infection in immunocompetent humans. 1 The development of cryptococcal meningitis occurs mainly in immunocompromised HIV-1-infected patients, most likely by reactivation of latent pulmonary C. neoformans infection. 2 It is estimated that 504,000 HIV-1-infected patients die every year from cryptococcal meningitis in sub-Saharan Africa, 3 which surprisingly exceeds the annual death rate of tuberculosis-associated HIV cases. Resistance against C. neoformans primarily involves monocytic effector mechanisms. 4 -6 In this context, T helper (Th) cells are central regulatory players with profound effects. Whereas IL-12-dependent Th1 responses are protective, with an additional contribution by IL-23-dependent Th17 responses, 7-9 Th2 cells producing IL-4, IL-13, and IL-5 are detrimental. 10,11 Studies 12-14 that used i.v. inoculation examined the traversal of the blood-brain barrier by C. neoformans and led to the conclusion that transmigration can occur with intracellular and extracellular fungi. In case of bronchopulmonary infection, dissemination seems to rely more on Th2 cytokines. This allergic Th2-driven inflammation represents the immunopathological pathway promoting disease by allowing cryptococci to grow inside the lung and finally enabling dissemination to the brain, ultimately causing fatal meningoencephalitis. 15 This sequela is accompanied by development of IL-4/IL-13-dependent alternatively activated macrophages, suggesting that those cells may be involved in dissemination. Alternatively activated macrophages are found only in susceptible mice 15 and show significantly reduced control of intracellular growth. 5 In addition, IL-13-dependent mucus production by goblet cells, IL-4 -...

Impact of Surfactant Protein D, Interleukin-5, and Eosinophilia on Cryptococcosis

“…Along with the widely published fact that eosinophilia has often been associated with ineffective immune responses against C. neoformans, it has been shown that eosinophils bind C. neoformans in the presence of opsonizing antibodies (41), that late-phase C. neoformans-induced pulmonary eosinophilia is IL-5 dependent (8), and that eosinophils have C. neoformans-derived antigen-presenting capabilities (42,43). Recently eosinophils were found to be important producers of IL-4 and thus are contributors to nonprotective Th2 responses (44). It has remained unclear whether IL-5 and eosinophils are mere bystanders during an otherwise pathogenic Th2 process or whether they were active contributors to C. neoformans disease.…”

IL-33 Priming Regulates Multiple Steps of the Neutrophil-Mediated Anti-Candida albicans Response by Modulating TLR and Dectin-1 Signals

“…IL-33 acts on a variety of cells of the innate arm of immunity, including neutrophils, macrophages, dendritic cells, mast cells, basophils, and eosinophils, and functions as an amplifier of inflammation (5)(6)(7)(8)(9)(10)(11)(12)(13). Recent studies have suggested that IL-33 plays a role in infection-related inflammation, as IL-33 is protective against infection by opportunistic pathogens such as Pseudomonas aeruginosa, Pneumocystis murina, Cryptococcus neoformans, and polymicrobes (6,8,9,14). Prior to this study, there had been no publications regarding the role of IL-33 in Candida albicans infections.…”

TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

“…Following intratracheal C. neoformans infection, genetically susceptible C57BL/6 mice were shown to have marked IL-5-dependent eosinophil recruitment that was associated with crystal deposition and airway epithelial damage (44). Eosinophils were also shown to produce IL-4, which promotes Th2 responses and contributes to immunopathology during pulmonary cryptococcal infection (40). Conversely, despite the ability to internalize and kill C. neoformans in vitro (59,60), there is relatively little evidence that neutrophils contribute to protective host defense.…”

“…Equally important to host defense is a classical pattern of macrophage activation that aids in the elimination of cryptococcal cells (36)(37)(38). In contrast, susceptibility to progressive cryptococcal disease is characterized by a Th2 pattern of cytokine expression, lung eosinophilia, goblet cell metaplasia, and alternative macrophage activation (39)(40)(41).…”