RÉSUMÉ
We previously reported that combination treatment with fingolimod (FTY720) plus antigenic peptide of glucose-6-phosphate isomerase (residues 325-339) (GPI325-339) from the onset of symptoms significantly inhibited disease progression in a mouse model of GPI325-339-induced arthritis. In this study, we investigated the mechanism(s) involved. The model mice were treated from arthritis onset with FTY720 alone, GPI325-339 alone, or the combination of FTY720 plus GPI325-339. At the end of treatment, inguinal lymph nodes (LNs) were excised and examined histologically and in flow cytometry. Levels of apoptotic cells, programmed death-1-expressing CD4(+)forkhead box P3(-) nonregulatory T cells (non-Tregs), and cytotoxic T-lymphocyte antigen 4-expressing non-Tregs in inguinal LNs were markedly increased in the combination treatment group mice. Regulatory T cells (Tregs) were also increased. These results indicate that combination treatment with FTY720 plus GPI325-339 inhibits the progression of arthritis by inducing clonal deletion and anergy of pathogenic T cells and also by immune suppression via Tregs.
Sujet(s)
Antigènes , Arthrite expérimentale , Polyarthrite rhumatoïde , Chlorhydrate de fingolimod/pharmacologie , Glucose 6-phosphate isomerase , Tolérance immunitaire/effets des médicaments et des substances chimiques , Immunosuppresseurs/pharmacologie , Animaux , Antigènes/immunologie , Antigènes/pharmacologie , Antigènes/usage thérapeutique , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/immunologie , Polyarthrite rhumatoïde/traitement médicamenteux , Polyarthrite rhumatoïde/immunologie , Lymphocytes T CD4+/métabolisme , Association thérapeutique , Modèles animaux de maladie humaine , Évolution de la maladie , Chlorhydrate de fingolimod/usage thérapeutique , Glucose 6-phosphate isomerase/immunologie , Glucose 6-phosphate isomerase/pharmacologie , Glucose 6-phosphate isomerase/usage thérapeutique , Immunosuppresseurs/usage thérapeutique , Mâle , Souris de lignée DBA , Peptides/immunologie , Peptides/pharmacologie , Peptides/usage thérapeutique , Lymphocytes T régulateurs/métabolismeRÉSUMÉ
Dendritic cells (DCs) play essential roles in both innate and adaptive immune responses. In addition, mutual regulation of the nervous system and immune system is well studied. One of neuropeptides, calcitonin gene-related peptide (CGRP), is a potent regulator in immune responses; in particular, it has anti-inflammatory effects in innate immunity. For instance, a deficiency of the CGRP receptor component RAMP 1 (receptor activity-modifying protein 1) results in higher cytokine production in response to LPS (lipopolysaccharide). On the other hand, how CGRP affects DCs in adaptive immunity is largely unknown. In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin-induced delayed-type hypersensitivity (DTH) model. CGRP also down-regulated the expressions of chemokine receptor CCR2 and its ligands CCL2 and CCL12 in DCs. Intriguingly, the frequency of migrating CCR2(+) DCs in draining lymph nodes of RAMP1-deficient mice was higher after DTH immunization. Moreover, these CCR2(+) DCs highly expressed IL-12 and CD80, resulting in more effective induction of Th1 differentiation compared with CCR2(-) DCs. These results indicate that CGRP regulates Th1 type reactions by regulating expression of cytokines, chemokines, and chemokine receptors in DCs.
Sujet(s)
Peptide relié au gène de la calcitonine/immunologie , Cellules dendritiques/immunologie , Hypersensibilité retardée/immunologie , Animaux , Antigène CD80/immunologie , Différenciation cellulaire/immunologie , Chimiokine CCL2/immunologie , Régulation négative/immunologie , Interleukine-12/immunologie , Souris , Souris de lignée BALB C , Protéines chimioattractives monocytaires/immunologie , Protéine-1 modifiant l'activité des récepteurs/immunologie , Récepteurs CCR2/immunologie , Lymphocytes auxiliaires Th1/immunologieRÉSUMÉ
Th9 cells are a novel Th cell subset that produces IL-9 and is involved in type I hypersensitivity such as airway inflammation. Although its critical roles in asthma have attracted interest, the physiological regulatory mechanisms of Th9 cell differentiation and function are largely unknown. Asthma is easily affected by psychological factors. Therefore, we investigated one of the physiological mediators derived from the nervous system, calcitonin gene-related peptide (CGRP), in asthma and Th9 cells because CGRP and activation of the cAMP/protein kinase A (PKA) pathway by CGRP are known to be important regulators in several immune responses and allergic diseases. In this study, we demonstrated that the CGRP/cAMP/PKA pathway promotes IL-9 production via NFATc2 activation by PKA-dependent glycogen synthase kinase-3ß inactivation. Moreover, CGRP also induces the expression of PU.1, a critical transcriptional factor in Th9 cells, which depends on PKA, but not NFATc2. Additionally, we demonstrated the physiological importance of CGRP in IL-9 production and Th9 differentiation using an OVA-induced airway inflammation model and T cell-specific CGRP receptor-deficient mice. The present study revealed a novel regulatory mechanism comprising G protein-coupled receptor ligands and nervous system-derived substances in Th9 cell differentiation and type I hypersensitivity.