RESUMO
Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice. Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1ß, whereas production of IL-10 and IFN-ß is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a-/- bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.
Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Membrana Celular/metabolismo , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Mycobacterium bovis/fisiologia , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Ácido Aspártico Endopeptidases/genética , Bovinos , Células Cultivadas , Citocinas/metabolismo , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Imunidade , Imunomodulação , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/imunologia , Tuberculose BovinaRESUMO
TWE-PRIL is a naturally occurring fusion protein of components of two TNF superfamily members: the extracellular domain of APRIL; and the intracellular and transmembrane domains of TWEAK with no known function. Here, we show that April-/- mice (which lack APRIL and TWE-PRIL) exhibited overgrowth of sympathetic fibres in vivo, and sympathetic neurons cultured from these mice had significantly longer axons than neurons cultured from wild-type littermates. Enhanced axon growth from sympathetic neurons cultured from April-/- mice was prevented by expressing full-length TWE-PRIL in these neurons but not by treating them with soluble APRIL. Soluble APRIL, however, enhanced axon growth from the sympathetic neurons of wild-type mice. siRNA knockdown of TWE-PRIL but not siRNA knockdown of APRIL alone also enhanced axon growth from wild-type sympathetic neurons. Our work reveals the first and physiologically relevant role for TWE-PRIL and suggests that it mediates reverse signalling.
