Receptor interacting protein 3 kinase, not 1 kinase, through MLKL-mediated necroptosis is involved in UVA-induced corneal endothelium cell death

Abstract

Ultraviolet (UV) is one of the most energetic radiations in the solar spectrum that can result in various tissue injury disorders. Previous studies demonstrated that UVA, which represents 95% of incident photovoltaic radiation, induces corneal endothelial cells (CECs) death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor-interacting protein 3 kinase (RIPK3), a key signaling molecule of PCD, in UVA-induced injury using a short-term corneal endothelium (CE) culture model. UVA irradiation activated RIPK3 and mediated necroptosis both in mouse CE and primary human CECs (pHCECs). UVA irradiation was associated with upregulation of key necroptotic molecules (DAI, TRIF, and MLKL) that lie downstream of RIPK3. Moreover, RIPK3 inhibition or silencing in primary corneal endothelial cells suppresses UVA-induced cell death, along with downregulation of MLKL in pHCECs. In addition, genetic inhibition or knockout of RIPK3 in mice (RIPK3K51A and RIPK3−/− mice) similarly attenuates cell death and the levels of necroptosis in ex vivo UVA irradiation experiments. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced cell death in CE and indicate its potential as a future protective target.

MLKL, a new actor of UVB-induced apoptosis in human diploid dermal fibroblasts

“…However, previous data showed that RIPK3 transcripts is increased in NHDF treated by chronic UVB doses [32], making RIPK3 a protein of interest in the study of cell response to UVB. RIPK3, through MLKL-mediated necroptosis, was found to be involved in UVA-induced retina and cornea cell death [33,34]. Those results led us to investigate the involvement of RIPK3 and MLKL in UVBinduced cell death in NHDF.…”

Extracellular Vesicles in Corneal Fibrosis/Scarring

“…Over the past decade, different approaches in treating ocular-related diseases by gene silencing [ 141 , 142 , 143 ], drugs [ 144 , 145 , 146 ], and oxygenating technologies targeting particularly the wound-healing mechanism [ 147 , 148 ] have been explored. There has been some success, yet further research is warranted for novel treatments and cell-free EV based therapy is emerging as a promising approach because of its advantages over ongoing options in many diseases [ 135 , 139 , 149 , 150 ].…”

Advances in biomaterials for the treatment of retinoblastoma

“…Although there have been approaches focused on silencing genes associated with cancer and subsequent cessation of tumor growth and metastasis 156,[225][226][227] residual side effects Nanomedicine is a hot topic in biotechnology that is centered on developing nanocarriers for prophylactic, diagnostic, and therapeutic uses and is a field of science that revolutionized cancer diagnosis and treatment. Nanocarriers are nanosized particles (1-100 nm in diameter) intended to selectively transport anticancer drugs into the tumor site.…”

“…For example, liposomes, 219,220 proteins, 221 polymers, 222 hydrogels, 223 inorganic NPs, 224 and other nanocarriers, play a crucial role in the delivery of chemotherapeutic agents and other modulators to induce an effective treatment for cancer. Although there have been approaches focused on silencing genes associated with cancer and subsequent cessation of tumor growth and metastasis 156,225–227 residual side effects and multidrug resistance remain concerns, there remain concerns about the residual side effects and the development of multidrug resistance.…”