Gherardi Romain Kroum, Eidi Housam, Crépeaux Guillemette, Authier François Jerome, Cadusseau Josette
Faculté de Médecine and Faculté des Sciences et Technologie, INSERM U955 Team 10, Université Paris Est-Créteil , Créteil , France.
Front Neurol. 2015 Feb 5;6:4. doi: 10.3389/fneur.2015.00004. eCollection 2015.
Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunological adjuvant of vaccines. Concerns linked to the use of alum particles emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome. MMF revealed an unexpectedly long-lasting biopersistence of alum within immune cells in presumably susceptible individuals, stressing the previous fundamental misconception of its biodisposition. We previously showed that poorly biodegradable aluminum-coated particles injected into muscle are promptly phagocytosed in muscle and the draining lymph nodes, and can disseminate within phagocytic cells throughout the body and slowly accumulate in brain. This strongly suggests that long-term adjuvant biopersistence within phagocytic cells is a prerequisite for slow brain translocation and delayed neurotoxicity. The understanding of basic mechanisms of particle biopersistence and brain translocation represents a major health challenge, since it could help to define susceptibility factors to develop chronic neurotoxic damage. Biopersistence of alum may be linked to its lysosome-destabilizing effect, which is likely due to direct crystal-induced rupture of phagolysosomal membranes. Macrophages that continuously perceive foreign particles in their cytosol will likely reiterate, with variable interindividual efficiency, a dedicated form of autophagy (xenophagy) until they dispose of alien materials. Successful compartmentalization of particles within double membrane autophagosomes and subsequent fusion with repaired and re-acidified lysosomes will expose alum to lysosomal acidic pH, the sole factor that can solubilize alum particles. Brain translocation of alum particles is linked to a Trojan horse mechanism previously described for infectious particles (HIV, HCV), that obeys to CCL2, signaling the major inflammatory monocyte chemoattractant.
氢氧化铝（明矾）是一种晶体化合物，广泛用作疫苗的免疫佐剂。在认识到明矾颗粒在肌痛性脑脊髓炎/慢性疲劳综合征患者中检测到的所谓巨噬细胞性肌炎（MMF）病变中的致病作用后，出现了与使用明矾颗粒相关的担忧。MMF揭示了在可能易感个体的免疫细胞中明矾具有出乎意料的长期生物持久性，强调了之前对其生物处置的基本误解。我们之前表明，注入肌肉的难生物降解的铝包被颗粒会迅速在肌肉和引流淋巴结中被吞噬，并可在全身的吞噬细胞内扩散并缓慢积聚在大脑中。这强烈表明，吞噬细胞内佐剂的长期生物持久性是缓慢的脑转运和延迟神经毒性的先决条件。了解颗粒生物持久性和脑转运的基本机制是一项重大的健康挑战，因为这有助于确定导致慢性神经毒性损伤的易感因素。明矾的生物持久性可能与其溶酶体不稳定作用有关，这可能是由于晶体直接诱导吞噬溶酶体膜破裂所致。持续在其细胞质中感知外来颗粒的巨噬细胞可能会以个体间效率各异的方式反复进行一种特殊形式的自噬（异噬），直到它们处理掉外来物质。颗粒在双膜自噬体中的成功分隔以及随后与修复和重新酸化的溶酶体融合，将使明矾暴露于溶酶体酸性pH值下，这是唯一能够溶解明矾颗粒的因素。明矾颗粒的脑转运与先前针对感染性颗粒（HIV、HCV）描述的特洛伊木马机制有关，该机制受CCL2调控，CCL2是主要的炎症单核细胞趋化因子。
