RESUMEN
Hypersensitivity pneumonitis is characterized by pulmonary accumulation of B-cell-rich tertiary lymphoid tissues (TLTs), which are alleged sites of amplification for antigen-specific responses. The sphingosine-1-phosphate receptor 1 (S1P1) regulates key mechanisms underlying lymphoid tissue biology and its chemical modulation causes lymphocyte retention in lymph nodes. Given the putative immunopathogenic impact of lymphocyte accumulation in TLTs, we investigated whether or not chemical modulation of S1P1 caused lymphocyte retention within TLTs in a model of hypersensitivity pneumonitis. Mice were exposed subchronically to Methanosphaera stadtmanae (MSS) in order to induce an hypersensitivity pneumonitis-like disease. MSS exposure induced B-cell-rich TLTs surrounded by S1P1-positive microvessels. Upon MSS rechallenge, the S1P1 agonist RP001 prevented the pulmonary increase of CXCL13, a chief regulator of B-cell recruitment in lymphoid tissues. This was associated with a complete inhibition of MSS rechallenge-induced TLT enlargement and with a 2.3-fold reduction of MSS-specific antibody titers in the lung. Interference with TLT reactivation was associated with a 77% reduction of neutrophil accumulation and with full inhibition of protein-rich leakage in the airways. Thus, an S1P1 agonist hinders TLT enlargement upon antigenic rechallenge and inhibits key pathognomonic features of experimental hypersensitivity pneumonitis.
Asunto(s)
Alveolitis Alérgica Extrínseca/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Pulmón/inmunología , Tejido Linfoide/efectos de los fármacos , Methanobacteriaceae/inmunología , Receptores de Lisoesfingolípidos/agonistas , Alérgenos/inmunología , Alveolitis Alérgica Extrínseca/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/inmunología , Linfocitos B/inmunología , Movimiento Celular , Quimiocina CXCL13/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Activación de Linfocitos , Tejido Linfoide/inmunología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Esfingosina-1-FosfatoRESUMEN
Allergic asthma is a chronic inflammatory disorder characterized by eosinophilia and T helper type 2 (Th2) cell activation. However, little information is available on the mechanisms leading to this pathology. We previously showed that alveolar macrophages (AM) from rats with experimental asthma lose their ability to prevent asthma symptoms. To understand the implication of AM in lung immunity, we investigated the influence of AM sensitization status on lung dendritic cell (DC) activation induced by allergen challenge in vivo. Rat sensitized to ovalbumin developed airway inflammation (eosinophils and Th2 cells) and demonstrated myeloid DC (mDC) activation following allergen exposure. The replacement of AM of sensitized animals by AM from naive animals did not affect allergen-triggered eosinophilia but completely abolished lung mDC allergen capture and migration to the lymph nodes, as well as Th2 cell polarization. Moreover, immunosuppressive functions of naive AM occurred in conjunction with low engulfment of allergens but without variation of major histocompatibility complex II and CD23 expression. Interestingly, sensitized AM that were withdrawn from the inflammatory environment regained their immunosuppressive functions when transferred to sensitized rats. Thus, these are the first in vivo evidences showing that dysregulation of AM functions is sufficient to induce DC-triggered allergic response.
Asunto(s)
Asma/inmunología , Células Dendríticas/inmunología , Macrófagos Alveolares/inmunología , Alérgenos/inmunología , Animales , Antígenos/inmunología , Asma/metabolismo , Células Dendríticas/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Homeostasis/inmunología , Inmunomodulación , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Activación de Linfocitos/inmunología , Activación de Macrófagos/inmunología , Macrófagos Alveolares/metabolismo , Ratas , Receptores de IgE/metabolismo , Linfocitos T/inmunología , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Structural damage and inflammation occur following tendon injury. The purpose of this study was to determine the time course of inflammatory cell accumulation in two animal models of acute tendinopathy. In the first model, rat Achilles tendons were exposed by blunt dissection, injected with collagenase and sacrificed at 1, 3, 7, 14 and 28 days. In the second model, collagenase was injected percutaneously and rats were sacrificed after 1 and 3 days. Sham animals were sacrificed at 1 and 3 days in both models. Neutrophil and ED1 macrophage populations increased by 46- and 18-fold, respectively, after 1 day in surgically exposed Achilles tendons (EAT) injected with collagenase. Neutrophils dropped by 70% while the concentration of ED1 macrophages remained constant at day 3 post-injury. Neutrophils and ED1+ macrophages returned to control values after 7 and 14 days, respectively. ED2+ macrophages showed a tendency to increase at day 28 although no significant difference was observed relative to ambulatory controls. Collagenase injected percutaneously reduced the extent of inflammation compared with operated animals. Thus, injured tendons exhibited a specific sequence of inflammatory cell accumulation which varied in intensity according to the modality used for collagenase injection.