Abstract
Chediak–Higashi syndrome, caused by mutations in the Lysosome Trafficking Regulator (Lyst) gene, is a recessive hypopigmentation disorder characterized by albinism, neuropathies, neurodegeneration, and defective immune responses, with enlargement of lysosomes and lysosome-related organelles. Although recent studies have suggested that Lyst mutations impair the regulation of sizes of lysosome and lysosome-related organelle, the underlying pathogenic mechanism of Chediak–Higashi syndrome is still unclear. Here we show striking evidence that deficiency in LYST protein function leads to accumulation of photoreceptor outer segment phagosomes in retinal pigment epithelial cells, and reduces adhesion between photoreceptor outer segment and retinal pigment epithelial cells in a mouse model of Chediak–Higashi syndrome. In addition, we observe elevated levels of cathepsins, matrix metallopeptidase (MMP) 3 and oxidative stress markers in the retinal pigment epithelium of Lyst mutants. Previous reports showed that impaired degradation of photoreceptor outer segment phagosomes causes elevated oxidative stress, which could consequently lead to increases of cysteine cathepsins and MMPs in the extracellular matrix. Taken together, we conclude that the loss of LYST function causes accumulation of phagosomes in the retinal pigment epithelium and elevation of several extracellular matrix-remodeling proteases through oxidative stress, which may, in turn, reduce retinal adhesion. Our work reveals previously unreported pathogenic events in the retinal pigment epithelium caused by Lyst deficiency. The same pathogenic events may be conserved in other professional phagocytic cells, such as macrophages in the immune system, contributing to overall Chediak–Higashi syndrome pathology.
Highlights
We show that the accumulation of phagosomes is associated with increased oxidative stress and an elevation of a group of proteases, including cathepsins B, L, and S, and matrix metalloprotease 3 (MMP3), which are likely secreted into the interphotoreceptor matrix (IPM) and may contribute to the retinal adhesion defect
We have identified a new mutant mouse bg-18 (B6.Cg-Lystbg-18J/Boc, JR#028230, The Jackson Laboratory) that recapitulates many of the pathologies observed in human Chediak–Higashi syndrome (CHS) patients and resembles the beige (Lystbg-J) mutant previously reported [22]
Consistent with previous reports, we found that the transcription levels of MMP3, and cathepsin B, L, and S assessed by quantitative real-time PCR, are increased in the retinal pigment epithelium (RPE) of the Lysosome Trafficking Regulator (Lyst) mutants relative to control (Fig 5A–5D)
Summary
Chediak–Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by albinism of the skin and hair, as well as hypopigmentation of the eye and additional eye pathologies including photophobia and macular hypoplasia associated with decreased visual acuity. The most detrimental pathology is, recurrent bacterial infections, which predominantly affect the respiratory tract, skin, and mucous membranes. These infections are due to the dysfunction of polymorphonuclear leukocytes [1,2,10,11]. The loss of LYST function results in enlarged lysosomes and lysosome-related organelles (LROs) in all cell types examined [1,14,16–22]. We examined the downstream effects of LYST dysfunction on the cellular pathology of the retinal pigment epithelium (RPE). The same mechanism is likely to exist in the immune system, where elevation of secreted proteases that cleave cell surface proteins, potentially leads to the reduced immune response observed in CHS [38]. Our results establish a series of events for the pathogenic mechanism of CHS and suggests an important new entry point for therapeutic intervention
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