RESUMO
Type I interferons (IFN-α and IFN-ß) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-ß and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-ß and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-ß and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.
Assuntos
Interferon beta/imunologia , Interferon gama/imunologia , Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Mycobacterium leprae/imunologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Humanos , Interferon beta/genética , Interferon beta/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/metabolismo , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/metabolismo , Viabilidade Microbiana , Monócitos/imunologia , Monócitos/metabolismo , Mycobacterium leprae/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transcriptoma , Tuberculose/genética , Tuberculose/imunologia , Regulação para Cima , beta-Defensinas/genética , beta-Defensinas/metabolismo , CatelicidinasRESUMO
It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.
Assuntos
Células Dendríticas/metabolismo , Interleucinas/metabolismo , Hanseníase/patologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Antígenos CD , Antígeno CD11b , Diferenciação Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucinas/farmacologia , Ligantes , Fatores Inibidores da Migração de Macrófagos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , RNA Mensageiro/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismoRESUMO
Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae-infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.