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Macrophage migration inhibitory factor is critical to interleukin-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection

Elizabeth S. Magalhães^*,1, Claudia N. Paiva^*,1, Heitor S. P. Souza, Alexandre S. Pyrrho, Diego Mourão-Sá^*, Rodrigo T. Figueiredo^*, Adriana Vieira-de-Abreu^¶, Helio S. Dutra, Mariana S. Silveira^||, Maria Ignez C. Gaspar-Elsas^#, Pedro Xavier-Elsas^*, Patrícia T. Bozza^¶ and Marcelo T. Bozza^*,2

^* Departamento de Imunologia, Instituto de Microbiologia,

Departamento de Clínica Médica Faculdade de Medicina,

Departamento de Farmácia, Instituto de Biologia,

Departamento de Histologia e Embriologia, Instituto de Ciências Biomédicas, and

^|| Laboratório de Neurogênese, Instituto de Biofísca, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and

^¶ Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, and

^# Departamento de Pediatria, Instituto Fernandes Figueira, Fiocruz, Rio de Janeiro, Brazil

²Correspondence: Departamento de Imunologia, Instituto de Microbiologia, CCS Bloco I, UFRJ. Avenida Carlos Chagas Filho, 373 Cidade Universitária, Rio de Janeiro, RJ, 21941–902 Brazil. E-mail: mbozza{at}micro.ufrj.br; mtbozza{at}gmail.com

Macrophage migration inhibitory factor (MIF) participates in the pathogenesis of inflammatory diseases, including asthma, in which it enhances airway hypersensitivity and tissue eosinophilia. Herein, we investigated the role of MIF in eosinophilopoiesis and tissue eosinophilia using Schistosoma mansoni infection. MIF-deficient (Mif^–/–) mice had similar numbers of adult worms, eggs, and granulomas compared to wild-type mice, but the size of granulomas was strikingly reduced due to smaller numbers of eosinophils. MIF did not affect the acquired response to infection, as Mif^–/– mice produced normal amounts of Th2 cytokines and IgE. Nevertheless, recombinant MIF (rMIF) behaved as a chemoattractant for eosinophils, what could partially explain the reduced eosinophilia in infected Mif^–/– mice. Moreover, the percentage of eosinophils was reduced in bone marrows of Mif^–/– mice chronically infected with S. mansoni compared to wild type. Mif^–/– had impaired eosinophilopoiesis in response to interleukin (IL)-5 and addition of rMIF to bone marrow cultures from IL-5 transgenic mice enhanced the generation of eosinophils. In the absence of MIF, eosinophil precursors were unable to survive the IL-5-supplemented cell culture, and were ingested by macrophages. Treatment with pancaspase inhibitor z-VAD or rMIF promoted the survival of eosinophil progenitors. Together, these results indicate that MIF participates in IL-5-driven maturation of eosinophils and in tissue eosinophilia associated with S. mansoni infection.—Magalhães, E. S., Paiva, C. N., Souza, H. S. P., Pyrrho, A. S., Mourão-Sá, D., Figueiredo, R. T., Vieira-de-Abreu, A., Dutra, H. S., Silveira, M. S., Gaspar-Elsas, M. I. C., Xavier-Elsas, P., Bozza, P. T., Bozza, M. T. Macrophage migration inhibitory factor is critical to IL-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection.

Key Words: Th2 response • apoptosis • inflammation • granuloma • MIF

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