Abstract
Timely and efficient elimination of apoptotic substrates, continuously produced during one’s lifespan, is a vital need for all tissues of the body. This task is achieved by cells endowed with phagocytic activity. In blood-separated tissues such as the retina, the testis and the ovaries, the resident cells of epithelial origin as retinal pigmented epithelial cells (RPE), testis Sertoli cells and ovarian granulosa cells (GC) provide phagocytic cleaning of apoptotic cells and cell membranes. Disruption of this process leads to functional ablation as blindness in the retina and compromised fertility in males and females. To ensure the efficient elimination of apoptotic substrates, RPE, Sertoli cells and GC combine various mechanisms allowing maintenance of tissue homeostasis and avoiding acute inflammation, tissue disorganization and functional ablation. In tight cooperation with other phagocytosis receptors, MERTK—a member of the TAM family of receptor tyrosine kinases (RTK)—plays a pivotal role in apoptotic substrate cleaning from the retina, the testis and the ovaries through unconventional autophagy-assisted phagocytosis process LAP (LC3-associated phagocytosis). In this review, we focus on the interplay between TAM RTKs, autophagy-related proteins, LAP, and Toll-like receptors (TLR), as well as the regulatory mechanisms allowing these components to sustain tissue homeostasis and prevent functional ablation of the retina, the testis and the ovaries.
Highlights
Every day, around 20–50 billion cells die by apoptosis and have to be eliminated from the body in order to maintain homeostasis and to avoid the autoimmune response against intracellular antigens [1,2]
Several excellent reviews are available to date [3,4]; here we will only briefly touch upon the general information regarding phagocytosis process per se, and focus on phagocytosis mediated by c-mer proto-oncogene tyrosine kinase (MERTK) in blood-separated tissues
Electrophysiological assessment of animals 30 days after injection revealed the increased sensitivity of treated eyes to low-intensity light. These results provided definitive evidence that the mutation of Mer tyrosine kinase (Mertk) underlies the Royal College of Surgeons (RCS) retinal dystrophy phenotype, and that the phenotype can be corrected by the treatment of juvenile animals [72]
Summary
Among blood-separated tissues, the retina, the testis and the ovaries manifest the highest rate of the production of apoptotic substrates, requiring efficient machinery for their removal. 250 × 106 residual bodies (RB), which are the fragments of apoptotic membranes detached from elongated spermatids [16], are produced daily by the mammalian testis Both apoptotic germ cells and RB are ingested and destroyed by the somatic Sertoli cells [17,18], which are “nurse” cells of the testis, forming a part of a seminiferous tubule and supporting the process of spermatogenesis [19]. Autophagy was classically defined as the starvation survival mechanism, endowing cells with the ability to auto digest This mechanism allows the degradation and reuse of the portions of cell cytoplasm in support of vital functions [23,24]. LC3-II is a specific autophagy marker currently used to monitor autophagy [34]
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