RESUMO
Iron is known not only for its importance in cellular and metabolic pathways but also for its role in causing cellular toxicities such as production of reactive oxygen species and growth of pathogens. The inability of the human body to physiologically excrete excess iron highlights the need to develop a cheap yet effective iron chelator. This study provides initial evidence of the therapeutic and prophylactic properties of 3-hydroxypyridin-4-one (HPO) chelators in murine collagen-induced arthritis. To determine whether these chelators would be effective on human cells, we tested a panel of different HPO chelators and identified 7-diethylamino-N-((5-hydroxy-6-methyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-N-methyl-2-oxo-chromen-3-carboxamide (CP655) as the most effective compound targeting human CD4+ T cells. Treatment with CP655 causes significant inhibition of cell proliferation and production of inflammatory cytokines such as interferon-γ and interleukin-17. Microarray analysis revealed dysregulation in cell cycle-related genes following CP655 treatment. This was validated by flow cytometry demonstrating a G1/S phase block caused by CP655. Finally, mechanistic experiments revealed that the chelator may be causing an upregulation of the cell cycle inhibitor protein CDKN1A (p21) as a possible mechanism of action. In conclusion, this study demonstrates that HPO chelators could prove to have therapeutic potential for diseases driven by excessive T cell proliferation.
Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fase S , Animais , Ciclo Celular/efeitos dos fármacos , Humanos , Ferro , Quelantes de Ferro/farmacologia , Camundongos , Fase S/efeitos dos fármacos , Regulação para CimaRESUMO
The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk.SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.
Assuntos
Dor Crônica/fisiopatologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Nociceptores/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Comunicação Celular , Células Cultivadas , Dor Crônica/induzido quimicamente , Meios de Cultivo Condicionados/farmacologia , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/farmacologia , Nociceptores/fisiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/efeitos dos fármacos , Fator de Transcrição STAT5/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2-/-) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2-/- mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.
Assuntos
Gânglios Espinais/fisiopatologia , Imunoglobulina G/administração & dosagem , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Dor Nociceptiva/imunologia , Dor Nociceptiva/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Células Cultivadas , Feminino , Humanos , Imunização Passiva , Masculino , Mecanotransdução Celular , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Células do Corno Posterior/fisiologia , Superfamília Shaker de Canais de Potássio/fisiologiaRESUMO
There is burgeoning interest in the interaction between the immune and nervous systems. Pain is mediated by primary sensory neurons (nociceptors) that can respond to a variety of thermal, mechanical and chemical signals. Cytokines are now recognized as important mediators of inflammatory pain. They can induce nociceptor sensitization indirectly via mediators, wherein neurons become primed and thus become more responsive to stimulation; alternatively, there is also evidence that cytokines can directly activate neurons via their specific receptors present on the neuronal cells. We review here the evidence for and against these respective mechanisms, focusing on arthritis and inflammatory skin models. A number of striking inconsistencies amongst the conclusions made in the literature are highlighted and discussed.
Assuntos
Artrite/imunologia , Citocinas/metabolismo , Inflamação Neurogênica/imunologia , Nociceptores/fisiologia , Dor/imunologia , Receptores de Citocinas/metabolismo , Pele/imunologia , Animais , Modelos Animais de Doenças , HumanosRESUMO
Chronic pain affects more than 20% of the UK population. Neurotrophic factors have been identified as therapeutic targets to improve current treatments of chronic pain. This review article focuses on nerve growth factor (NGF) and interleukin-6 (IL-6) as potential therapeutic targets. In this review we highlight the mechanisms of action and the current progress of targeted therapies in clinical trials.
Assuntos
Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Fator de Crescimento Neural/antagonistas & inibidores , Fator de Crescimento Neural/metabolismo , Animais , HumanosRESUMO
The 2nd annual conference organized by EuroSciCon was aimed at understanding the various roles played by regulatory cells in autoimmunity. Several eminent researchers from all over Europe presented their novel findings at this conference. The presentations covered a wide range of topics from rheumatoid arthritis to multiple sclerosis to membrane lipids and environmental factors affecting immune responses.