RESUMEN
Inflammatory diseases are characterized by dysregulated cytokine production. Altered functions for most risk loci, including the inflammatory bowel disease and leprosy-associated tumor necrosis factor ligand superfamily member 15 (TNFSF15) region, are unclear. Regulation of pattern-recognition-receptor (PRR)-induced signaling and cytokines is crucial for immune homeostasis; TNFSF15:death receptor 3 (DR3) contributions to PRR responses have not been described. We found that human macrophages expressed DR3 and that TNFSF15:DR3 interactions were critical for amplifying PRR-initiated MAPK/NF-κB/PI3K signaling and cytokine secretion in macrophages. Mechanisms mediating TNFSF15:DR3 contributions to PRR outcomes included TACE-induced TNFSF15 cleavage to soluble TNFSF15; soluble TNFSF15 then led to TRADD/FADD/MALT-1- and caspase-8-mediated autocrine IL-1 secretion. Notably, TNFSF15 treatment also induced cytokine secretion through a caspase-8-dependent pathway in intestinal myeloid cells. Importantly, rs6478108 A disease risk-carrier macrophages demonstrated increased TNFSF15 expression and PRR-induced signaling and cytokines. Taken together, TNFSF15:DR3 interactions amplify PRR-induced signaling and cytokines, and the rs6478108 TNFSF15 disease-risk polymorphism results in a gain of function.
Asunto(s)
Caspasa 8/metabolismo , Predisposición Genética a la Enfermedad , Interleucina-1/metabolismo , Polimorfismo de Nucleótido Simple/genética , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetilmuramil-Alanil-Isoglutamina/farmacología , Células Cultivadas , Humanos , Ligandos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mycobacterium/metabolismo , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , FN-kappa B/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal/efectos de los fármacos , Solubilidad , Inhibidor Tisular de Metaloproteinasa-3/metabolismoRESUMEN
Matrix metalloproteinases (MMPs) and tumor necrosis factor alpha (TNF-alpha) play important and related roles in the pathogenesis of nerve injury. MMP-dependent and TNF-alpha-dependent processes of neurodegeneration, such as blood-nerve breakdown and immune cell recruitment, are characteristic of leprosy nerve damage. Our work has contributed to the understanding of the role of cytokines in the process, but the role of MMPs in the pathogenesis of neuritic leprosy has not been investigated. This study analyzed the changes in mRNA expression and immunodistribution of MMP-2, MMP-9, TNF-alpha-converting enzyme (TACE), TNF-alpha in nerves of 27 pure neuritic leprosy (PNL) patients, both acid-fast bacilli positive (AFB(+)) and acid-fast bacilli negative (AFB(-)), and 8 non-leprosy patients with control peripheral neuropathic conditions. MMP-2, MMP-9, and TNF-alpha mRNA expression was significantly induced in the AFB(-) relative to the AFB(+) neuritic leprosy group and nonlepritic controls; TACE levels were also elevated in the AFB(-) group, but this change was not statistically significant. Immunoreactive profiles for TNF-alpha and MMPs demonstrated strong reactivity of myelinated axons, infiltrating macrophages, Schwann cells, endothelial cells, and perineurial cells in neuritic leprosy biopsies. This study provides the evidence of the involvement of MMPs in the pathogenesis of PNL neuropathy.