RESUMO
BACKGROUND: Both the parasympathetic and sympathetic nervous system exert control over innate immune responses. In inflammatory bowel disease, sympathetic innervation in intestinal mucosa is reduced. Our aim was to investigate the role of sympathetic innervation to the intestine on regulation of the innate immune responses. METHODS: In lipopolysaccharide (LPS)-stimulated macrophages, we evaluated the effect of adrenergic receptor activation on cytokine production and metabolic profile. In vivo, the effect of sympathetic denervation on mucosal innate immune responses using 6-hydroxydopamine (6-OHDA), or using surgical transection of the superior mesenteric nerve (sympathectomy) was tested in Rag1-/- mice that lack T- and B-lymphocytes. RESULTS: In murine macrophages, adrenergic ß2 receptor activation elicited a dose-dependent reduction of LPS-induced cytokines, reduced LPS-induced glycolysis and increased maximum respiration. Sympathectomy led to a significantly decreased norepinephrine concentration in intestinal tissue. Within 14 days after sympathectomy, mice developed clinical signs of colitis, colon oedema and excess colonic cytokine production. Both 6-OHDA and sympathectomy led to prominent goblet cell depletion and histological damage of colonic mucosa. CONCLUSIONS: We conclude that the sympathetic nervous system plays a regulatory role in constraining innate immune cell reactivity towards microbial challenges, likely via the adrenergic ß2 receptor.
Assuntos
Colite/imunologia , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/inervação , Sistema Nervoso Simpático/imunologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/farmacologia , Animais , Células Cultivadas , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxidopamina/farmacologiaRESUMO
Vagal nerve efferent activation has been shown to ameliorate the course of many inflammatory disease states. This neuro-modulatory effect has been suggested to rest on acetylcholine receptor (AChR) activation on tissue macrophages or dendritic cells (DCs). In more recent studies, vagal anti-inflammatory activity was shown involve adrenergic, splenic, pathways. Here we provide evidence that the adrenergic, rather than cholinergic, receptor activation on bone marrow derived DCs results in enhanced endocytosis uptake, enhanced IL-10 production but a decreased IL-6, IL-12p70 and IL-23 production. In antigen specific T cell stimulation assays, adrenergic ß2 receptor activation on bone marrow DCs led to an enhanced potential to induce Foxp3 positive suppressive Treg cells. These effects were independent of IL10-R activation, TGFß release, or retinoic acid (RA) secretion. Hence, adrenergic receptor ß2 activation modulates DC function resulting in skewing towards anti-inflammatory T cell phenotypes.
Assuntos
Citocinas/metabolismo , Células Dendríticas/metabolismo , Mediadores da Inflamação/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Dextranos/farmacocinética , Endocitose/efeitos dos fármacos , Epinefrina/farmacologia , Feminino , Citometria de Fluxo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Fatores de Transcrição Forkhead/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos beta 2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismoRESUMO
Antigen presenting cells like dendritic cells (DC) are responsible for the initiation of adaptive immune responses via the T helper cells they activate. The type of T cell responses DC induce is dependent on the local immunological environment where antigen has been taken up. In the gut, resident DC are phenotypically and functionally shaped by epithelial and stromal cell derived signals, the cytokine microenvironment, and neuronal products. These factors can control the activation state of DC thereby inducing tolerance for food and commensal organisms or immunity against pathogenic microbes. The enteric nervous system (ENS) is increasingly recognized as an important regulatory factor in intestinal immune cell control. Neurotransmitters and neuropeptides like acetylcholine (ACh), norepinephrine (NE) and vasoactive intestinal peptide (VIP) are released by neurons of the ENS and can affect the function of DC and subsequent immune responses. The critical balance between tolerance and protective immunity is disrupted in inflammatory bowel disease, which results in an exaggerated immune response against commensal bacteria. In this review we discuss the effects of ACh, VIP, and NE on DC function. DC express various receptors for these neuron derived products and can alter DC co-stimulatory molecule expression, cytokine release and subsequent T cell activation in an anti-inflammatory fashion. Knowledge about these interactions will help find new drug targets and may facilitate the development of specific therapies for diseases like inflammatory bowel disease (IBD).
Assuntos
Sistema Nervoso Autônomo/fisiologia , Células Dendríticas/fisiologia , Intestinos/imunologia , Neuroimunomodulação , Acetilcolina/fisiologia , Animais , Diferenciação Celular , Sistema Nervoso Entérico/fisiologia , Humanos , Inflamação/imunologia , Intestinos/citologia , Intestinos/inervação , Norepinefrina/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Transdução de Sinais , Sistema Nervoso Simpático/fisiologia , Linfócitos T/citologia , Linfócitos T/fisiologia , Peptídeo Intestinal Vasoativo/fisiologiaRESUMO
BACKGROUND: Chronic hepatitis C virus (HCV) infection is characterized by an insufficient immune response, possibly owing to impaired function of antigen-presenting cells such as myeloid dendritic cells (DCs). Therapeutic vaccination with in vitro generated DCs may enhance the immune response. Subsets of DCs can originate from monocytes, but the presence of HCV in monocytes that develop into DCs in vitro may impair DC function. Therefore, we studied the presence of HCV RNA in monocytes and monocyte-derived DCs from chronic HCV patients. METHODS: Monocytes were cultured with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) for 6 days, and then with GM-CSF, IL-4, tumour necrosis factor-alpha (TNF-alpha), prostaglandin E2, IL-1beta and IL-6 for 2 days to generate mature DCs. HCV RNA was assessed by polymerase chain reaction. Surface molecules were assessed by flow cytometry. Cytokine production was assessed by cytokine bead array. RESULTS: HCV RNA was present in monocytes in 11 of 13 patients, but undetectable in mature DCs in 13 of 13 patients. The morphology of patient DCs was comparable with DCs from healthy controls, but the percentage of cells expressing surface molecules CD83 (P=0.001), CD86 (P=0.023) and human leucocyte antigen-DR (P=0.028) was lower in HCV patients. Compared with control DCs, patient DCs produced enhanced levels of IL-10 (P=0.0079) and IL-8 (P=0.0079), and lower levels of TNF-alpha (P=0.032), IL-6 (P=NS) and IL-1beta (P=0.0079). Patient and control DCs did not produce IL-12. CONCLUSIONS: Monocyte-derived DCs from chronic HCV patients are not infected but show an immature phenotype and aberrant cytokine profile.