RESUMO
The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell-autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (IRI) stimulated endothelial cells to produce Hedgehog (Hh) ligands, which in turn induced the production of ZFYVE21 in a population of T memory cells with high amounts of the Hh receptor PTCH1 (PTCHhi cells, CD3+CD4+CD45RO+PTCH1hiPD-1hi), vigorous recruitment to injured endothelia, and increased effector responses in vivo. After priming by interferon-γ (IFN-γ), Hh-induced ZFYVE21 activated NLRP3 inflammasome activity in T cells, which potentiated IFN-γ responses. Hh-induced NLRP3 inflammasomes and T cell-specific ZFYVE21 augmented the vascular sequelae of chronic inflammation in mice engrafted with human endothelial cells or coronary arteries that had been subjected to IRI before engraftment. Moreover, the population of PTCHhi T cells producing high amounts of ZFYVE21 was expanded in patients with renal transplant-associated IRI, and sera from these patients expanded this population in control T cells in a manner that depended on Hh signaling. We conclude that Hh-induced ZFYVE21 activates NLRP3 inflammasomes in T cells, thereby promoting chronic inflammation.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Linfócitos T/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
BACKGROUND: Cognitive decline that occurs frequently in impaired glucose tolerance (IGT) may be largely due to endothelial dysfunction. We assessed: (i) the relationships between impact of urinary albumin excretion rate (UAER), as marker of generalized endothelial dysfunction, and cognition; (ii) if cognitive decline could be explained by arterial stiffening using pulse wave velocity (PWV). METHODS: One hundred forty older patients (age range 70-85 years) with IGT and no dementia were selected. Patients were classified according to 24-hour UAER: normoalbuminuric (NA) (UAER<20 microg/min) or microalbuminuric (MA) (UAER between 20 and 199 microg/min). Cognitive abilities were assessed by the Mini-Mental State Examination (MMSE) and a composite score of executive and attention functioning (CCS) at baseline and after 12 months of follow-up. RESULTS: In MA patients (n=80), increased UAERs correlated with intimal media thickness (IMT) (r=0.268; p=02) and PWV (r=0.310; p=004). In the same group, increased UAERs were correlated with MMSE and CCS even after adjusting for age and mean arterial blood pressure (MABP). After adding PWV, the associations among UAERs, MMSE, and CCS were no longer significant. In MA patients, PWV correlated with IMT, MMSE, and CCS. In NA patients, no significant correlations were found among UAERs, MMSE, and CCS. At follow-up, baseline UAERs predicted an approximately 20% risk of poor cognition (according to MMSE and CCS) after adjusting for confounders. After adding PWV, UAERs no longer predicted cognitive performance. CONCLUSIONS: MA older persons with IGT showed a decline in cognition performance that may be partially explained by arterial stiffness.
