RESUMO
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper-inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ-null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Proteína Quinase 12 Ativada por Mitógeno/imunologia , Proteína Quinase 13 Ativada por Mitógeno/imunologia , Células Mieloides/imunologia , Animais , Candida albicans/fisiologia , Candidíase/genética , Candidíase/microbiologia , Feminino , Interações Hospedeiro-Patógeno/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 12 Ativada por Mitógeno/deficiência , Proteína Quinase 12 Ativada por Mitógeno/genética , Proteína Quinase 13 Ativada por Mitógeno/deficiência , Proteína Quinase 13 Ativada por Mitógeno/genética , Células Mieloides/metabolismo , Células Mieloides/microbiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
Tbx3, a T-box gene family member related to the Drosophila gene optomotor blind (omb) and encoding a transcription factor, is expressed in anterior and posterior stripes in developing chick limb buds. Tbx3 haploinsufficiency has been linked with the human condition ulnar-mammary syndrome, in which predominantly posterior defects occur in the upper limb. Omb is expressed in Drosophila wing development in response to a signalling cascade involving Hedgehog and Dpp. Homologous vertebrate signals Sonic hedgehog (Shh) and bone morphogenetic protein 2 (Bmp2) are associated in chick limbs with signalling of the polarising region which controls anteroposterior pattern. Here we carried out tissue transplantations, grafted beads soaked in Shh, Bmps, and Noggin in chick limb buds, and analysed Tbx3 expression. We also investigated Tbx3 expression in limb buds of chicken and mouse mutants and retinoid-deficient quail in which anteroposterior patterning is abnormal. We show that Tbx3 expression in anterior and posterior stripes is regulated differently. Posterior Tbx3 expression is stable and depends on the signalling cascade centred on the polarising region involving Shh and Bmps, while anterior Tbx3 expression is labile and depends on the balance between positive Bmp signals, produced anteriorly, and negative Shh signals, produced posteriorly. Our results are consistent with the idea that posterior Tbx3 expression is involved in specifying digit pattern and thus provides an explanation for the posterior defects in human patients. Anterior Tbx3 expression appears to be related to the width of limb bud, which determines digit number.