Background
Globally, cataracts are the leading cause of blindness and account for nearly half (47.8%) of all blindness cases [
1,
2]. In a study in rural northern China, approximately 28.6% of participants aged 50 and older had poor postoperative visual outcomes, and cost was the most common barrier (73.9%) to cataract removal [
3]. To date, the only effective therapeutic method for cataracts is surgery, which has the potential for serious postoperative complications, e.g., increased intraocular pressure (IOP) and corneal edema. Hence, studies of cataractogenesis are vital for developing effective therapeutic modalities for the prevention and treatment of cataracts.
Cataracts are associated with a number of risk factors, e.g., drugs, malnutrition, aging, exposure to ultraviolet (UV) light, and diabetes mellitus [
4‐
6]. Short-wavelength blue light (400–500 nm) has attracted increasing attention because of its potential to injury the retina [
7,
8]. The relationship between the formation of cataracts and short-wavelength blue light exposure has been mentioned, but the evidence is inconclusive.
Apoptosis and pyroptosis rely on specific caspases to induce their respective programmed cell death pathways [
9]. Inflammatory caspases (caspases-1, − 4, − 5 and − 11) induce a form of necrotic programmed cell death, namely, pyroptosis, which is motivated by the canonical and noncanonical inflammasome signaling pathways [
10‐
14]. The activity of caspase-1 leads to the maturation of IL-1β and IL-18 and the cleavage of gasdermin D (GSDMD) to induce pore opening [
15‐
17]. Accumulating evidence has confirmed that pyroptosis is involved in the pathogenesis of both noninfectious and infectious diseases [
18,
19].
In the present study, we hypothesized that pyroptosis is involved in the pathogenesis associated with the occurrence and development of cataracts. A rat model of short-wavelength blue light exposure was established, and relative changes in pyroptosis factors in rat lens epithelial cells (LECs) were analyzed.
Discussion
LED light will gradually replace traditional incandescent light due to its considerable advantages, such as low power consumption and high light efficiency. However, the possible bio-photochemical injury to the eyes caused by LED light has also aroused public concern [
29]. Previous studies have shown that blue light induced oxidative stress and cellular damage in retinal tissues [
30‐
32]. In agreement with these findings, blue light-filtering IOLs have been thought to be a protective measure against blue light damage to the retina [
33]. Studies have confirmed that cumulative visible light exposure may accelerate the development of cataracts [
34]. Dysfunction of the LECs may lead to superficial cortical lens fiber edema and mature cataracts [
35].
An increasing number of studies have focused on elucidating the mechanisms of pyroptosis in different diseases. In our study, we report that after 6 weeks of short-wavelength blue LED lamp exposure, cataracts developed in the experimental rats. In addition, pyroptosis markers, including caspase-1, caspase-11, and GSDMD, were investigated. The present study showed that the expression levels of caspase-1, caspase-11 and GSDMD were significantly increased in rat LECs after 4, 8, and 12 weeks of exposure to a short-wavelength blue LED lamp. The results confirmed that pyroptosis may play a vital role in the formation of cataracts after short-wavelength blue light exposure.
Our present research demonstrated that cataracts had developed in the experimental rats after 6 weeks of blue light exposure. The clarity of the lens then progressively worsened with the duration of short-wavelength blue light exposure. The process of cataract formation illustrated in this study is consistent with that reported in an earlier study [
35]. In this study, the phenotype is a cataract involving lens fiber cells. The cell culture results also indicated that short-wavelength blue light can cause cell death in HLE-B3 hLECs with time.
A previous study demonstrated that pyroptosis participates in the oxidation of human LECs and may be involved in the initiation and progression of noncongenital cataracts. Caspase-1 plays an important role in the process of pyroptosis during the formation of cataracts [
36]. However, the role of short-wavelength blue light in the cataracts formation and the relative expression of pyroptosis markers, such as caspase-1, caspase-11, and GSDMD, in vivo is still unknown. In the present study, we demonstrated that short-wavelength blue light-induced activation of caspase-1, caspase-11, and GSDMD triggered cataracts in a pyroptosis-dependent manner.
Caspase-1, which is a crucial marker of the process of pyroptosis [
37], is activated by the NLRP3 inflammasome. Caspase-1 mediates proinflammatory programmed cell death in response to exogenous and endogenous stimuli to protect cells. The results of the current study show that caspase-1 expression levels were increased in short-wavelength blue light-exposed rat lens cells in a dose-dependent manner.
Most previous studies have focused on targeting the canonical inflammasome pathway. However, emerging studies have actively explored the regulatory role of the noncanonical caspase-11 inflammasome in noninfectious diseases. Studies have indicated that aging activates the NLRP1 inflammasome, resulting in the processing of caspase-1 and the upregulation of caspase-11 [
38]. Assembly and activation of the NLRP1 inflammasome involves caspase-1 and caspase-11 activation, which subsequently leads to the maturation and secretion of IL-1β and IL-18 [
39,
40]. In the present study, the qRT-PCR and Western blot analysis results showed increased expression of caspase-11 in rat LECs after short-wavelength blue light exposure. We hypothesize that caspase-11 might be activated by naturally occurring intracellular molecules under inflammatory conditions and that these intracellular inflammatory molecules might bind directly to caspase-11, subsequently activating caspase-11 noncanonical inflammasomes and leading to the pathogenesis of cataracts after short-wavelength blue light exposure. Further investigation is required to confirm this hypothesis.
Studies have revealed that GSDMD is activated by caspases − 1, − 4, − 5, and − 11, all of which split GSDMD into an N-terminal effector domain and a C-terminal inhibitory domain [
17,
41]. We found that the mRNA expression levels of GSDMD were increased, suggesting that pyroptosis was activated by short-wavelength blue light. Additional morphological evidence of gasdermin-mediated pore formation and membrane rupture in LEC pyroptosis is also needed.
Furthermore, we used annexin V-FITC/PI together with flow cytometry to analyze the percentage of viable cells and the pyroptosis of HLE-B3 cells after short-wavelength blue light exposure for different times. The evaluation method was a strength of this work. Our results suggested that short-wavelength blue light exposure caused pyroptotic death in HLE-B3 hLECs with time. As expected, the caspase-1 inhibitor may effectively suppress the formation of cataracts and defend against LEC damage by suppressing the caspase-1/GSDMD pathway under short-wavelength blue light exposure.
Our study has potential limitations. The increased levels of caspases and GSDMD in SD rats, which are nocturnal, and in the albino strain, do not thoroughly explain the association between short-wavelength blue light exposure and the formation of cataracts in humans. Other inflammatory responses in the cornea, conjunctiva, and anterior chamber must be investigated to understand the precise mechanism of cataract formation under short-wavelength blue light exposure. Second, the intensity and duration of the blue light used in the study were not physiologically relevant, and additional studies on the safety of long-term exposure to low levels of blue light are needed to determine the effects of blue light on the eye. Finally, although the increased level of caspase-1 may suggest that pyroptosis is involved in this process, it is difficult to determine whether other cell death types, such as apoptosis and necrosis, are concurrently involved in cataract formation in lens cells exposed to short-wavelength blue light. Therefore, further research is needed to address this issue. We will also focus on studying the pathogenesis of cataracts under short-wavelength blue light in vitro, and ROS changes will be included.
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