RESUMEN
Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kcnn4 is required for osteoclast and MGC formation in rodents and humans. Genetic deletion of Kcnn4 reduces macrophage multinucleation through modulation of Ca(2+) signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of Kcnn4 reduces experimental glomerulonephritis. Our data implicate Kcnn4 in macrophage multinucleation, identifying it as a potential therapeutic target for inhibition of bone resorption and chronic inflammation.
Asunto(s)
Artritis/metabolismo , Huesos/metabolismo , Núcleo Celular/fisiología , Glomerulonefritis/metabolismo , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/fisiología , Macrófagos/metabolismo , Animales , Artritis/patología , Resorción Ósea/metabolismo , Huesos/inmunología , Señalización del Calcio , Células Cultivadas , Redes Reguladoras de Genes , Glomerulonefritis/inmunología , Homeostasis , Humanos , Ratones Noqueados , Ratas Endogámicas Lew , Ratas Endogámicas WKY , Receptores Inmunológicos/metabolismoRESUMEN
Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several in vivo models. However, the effect of SYK inhibition on autoantibody production remains unclear, and SYK inhibition has not been studied in an autoimmune model of renal disease. We, therefore, studied the effect of SYK inhibition in experimental autoimmune GN, a rodent model of antiglomerular basement membrane disease. We show glomerular SYK expression and activation by immunohistochemistry in both experimental and clinical disease, and we show that treatment with fostamatinib, a small molecule kinase inhibitor selective for SYK, completely prevents the induction of experimental autoimmune GN. In established experimental disease, introduction of fostamatinib treatment led to cessation of autoantibody production, reversal of renal injury, preservation of biochemical renal function, and complete protection from lung hemorrhage. B cell ELISpot and flow cytometric analysis suggest that short-term fostamatinib treatment inhibits the generation and activity of antigen-specific B cells without affecting overall B-cell survival. Additionally, fostamatinib inhibited proinflammatory cytokine production by nephritic glomeruli ex vivo and cultured bone marrow-derived macrophages in vitro, suggesting additional therapeutic effects independent of effects on autoantibody production that are likely related to inhibited Fc receptor signaling within macrophages in diseased glomeruli. Given these encouraging results in an in vivo model that is highly applicable to human disease, we believe clinical studies targeting SYK in GN are now warranted.
Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/prevención & control , Formación de Anticuerpos/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Oxazinas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Piridinas/uso terapéutico , Aminopiridinas , Animales , Autoanticuerpos/sangre , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Morfolinas , Oxazinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinas , Ratas Endogámicas WKY , Bazo/efectos de los fármacos , Quinasa SykRESUMEN
It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.