RESUMO
In multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), myeloid cells comprise a major part of the inflammatory infiltrate in the central nervous system (CNS). We previously described that motile sperm domain-containing protein 2 (MOSPD2) is expressed on human myeloid cells and regulates monocyte migration in vitro. The role of MOSPD2 in EAE pathogenesis was studied by generating MOSPD2 knock-out (KO) mice and monoclonal antibodies directed against MOSPD2. We found that EAE development in MOSPD2 KO mice was significantly suppressed. While frequency representation of leukocyte subsets in lymphoid tissues was comparable, the ratio of inflammatory monocytes in the blood was markedly reduced in MOSPD2 KO mice. In addition, T cells from MOSPD2 KO mice displayed reduced secretion of proinflammatory cytokines and increased production of interleukin (IL)-4. Prophylactic and post-onset treatment using monoclonal antibodies (mAbs) generated against MOSPD2 abrogated development and reduced EAE severity. These results suggest that MOSPD2 is key in regulating migration of inflammatory monocytes, and that anti-MOSPD2 mAbs constitute a potential therapy for the treatment of CNS inflammatory diseases.
Assuntos
Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Esclerose Múltipla/metabolismo , Receptores de Quimiocinas/metabolismo , Linfócitos T/imunologia , Animais , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/terapia , Feminino , Humanos , Inflamação/genética , Inflamação/terapia , Interleucina-4/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/terapia , Receptores de Quimiocinas/genética , Equilíbrio Th1-Th2RESUMO
Atherosclerosis is an inflammatory disease of the vascular wall. Activated monocytes and dendritic cells (DC) in the intima layer of the vasculature promote atherogenesis. Toll-like receptor (TLR)-2 and TLR-4, which are predominantly expressed on these cells and mediate their activation, are essential for atherosclerosis development. In this study we demonstrate that VB-201, an oxidized phospholipid (Ox-PL) small molecule, inhibits TLR signalling restricted to TLR-2 and TLR-4 in human and mouse monocytes and DC. Mechanistically, we show that VB-201 binds directly to TLR-2 and CD14, the TLR-4 co-receptor, to impair downstream cues and cytokine production. In a rabbit model, oral administration of VB-201 constrained atherosclerosis progression. This effect was not due to reduced cholesterol abundance, as hyperlipidaemia was sustained. We suggest that VB-201 may counter inflammation where TLR-2 and/or CD14 complicity is essential, and is therefore beneficial for the treatment of atherosclerosis.