4.2.3. Inflammation

The general implication of iron in inflammation has been recently reviewed, and it will not be detailed here [109]. In RPE cells, the intracellular accumulation of iron activated the NRLP3 inflammasome pathway via the repression of the degradation of aluRNA by double-stranded RNA-specific endoribonuclease (DICER1). This mechanism involved the sequestration of the cofactor PCBP2 [110] and has been advocated in AMD. It has been also reported that iron induces the synthesis of complement C3 by activation of the Extracellular signal-regulated kinases (ERK)/SMAD3/CCAAT Enhancer Binding Protein Delta (CEBPD) 48 pathway [111]. The complement factor C5 carries between 13 and 15 iron atoms necessary for its conversion into an active form C5b by C5 convertase, a complex formed from the cleavage products of C3 [112], which shows the importance of iron in complement pathways activation, a recognized risk factor for AMD [113].

The prion protein (PrPC), the principal protein implicated in the pathogenesis of human and animal prion disorders, is also implied in retinal degeneration due to iron metabolism dysfunction. This neuronal protein is expressed in many tissues of the eye, such as the retina and the cornea trabeculum. PrP<sup>C</sup> is also expressed on the basolateral membrane of RPE, where it facilitates uptake of iron from choriocapillaries to neuroretina by functioning as a ferrireductase partner for divalent metal transporters. PrP-scrapie (PrP(Sc)), a misfolded isoform of this PrP<sup>C</sup> accumulates in the neuroretina resulting in iron accumulation [114].

In the brain, IL6 produced by microglia in response to lipopolysaccharide, induced the production of HEPC by astrocytes [115]. HEPC prevented the iron overload-activated neuronal apoptosis [115]. LPS induced also an HFE-independent expression of HEPC in MGC and in the RPE, both in vitro and in vivo. The increase in HEPC levels in retinal cells, occurring with a decrease in FPN levels, led to oxidative stress and apoptosis within the retina in vivo [116]. On the other hand, in both in vitro and in vivo models of amyloid β-induced pathology, HEPC downregulates the inflammatory and pro-oxidant processes in astrocytes and microglia and protected neurons from cell death [117]. Microglia and MGC activation associated with reactive gliosis has been observed in HJV knockout mice (*Hjv*−/− mice) with aging and subsequent retinal iron accumulation [37].

The role of LCN2 has been suspected in AMD where its expression is increased in aqueous humor and in the infiltrating cells present in the retina and choroid [118]. An age-related increase in LCN2 was described in RPE cells of Beta-crystallin A3 (Cryba1) conditional knockout mouse, a model of AMD associated with chronic inflammation response [49], but the exact implication of LCN2 in iron metabolism in these models remains to be studied.
