High myopia is a significant risk factor for several blinding eye diseases including glaucoma, retinal detachment, and macular degeneration, and therefore represents a leading cause of blindness worldwide (Buch et al., 2001). The prevalence of myopia is continuing to increase and is predicted to affect nearly half of the global population by 2050 (Holden et al., 2016). Although clinical and experimental studies indicate that normal eye growth (emmetropization) is controlled by visual input (Wallman and Winawer, 2004), the molecular mechanisms underlying myopia development in humans is not understood.

Animal models have provided valuable insights into the role of the visual environment in ocular growth control. Deprivation of form vision, through the use of visual ‘occluders’ or ‘goggles’ results in accelerated ocular growth and the development of myopia within a matter of days in many vertebrate species, including fish, chicks, mice, tree shrews, guinea pigs, and primates (Howlett and McFadden, 2006; Shen et al., 2005; Schaeffel et al., 2004; Tejedor and de la Villa, 2003; Troilo and Judge, 1993; Wallman et al., 1978; Sherman et al., 1977). Upon removal of the occluder, the elongated eye now experiences myopic defocus, which results in a rapid deceleration in ocular elongation and eventual return to emmetropia (recovery) (Wallman and Adams, 1987).

Postnatal ocular growth can also be manipulated through the application of positive or negative lenses, as the eye has been shown to compensate for the imposed defocus in many vertebrates, including fish, chicks, mice, mammals, and primates (Tkatchenko et al., 2010; Shen and Sivak, 2007; Norton et al., 2006; Graham and Judge, 1999; Hung et al., 1995; Schaeffel et al., 1988). Application of positive lenses results in images forming in front of the retina (myopic defocus). This imposed myopic defocus causes slowing of the rate of ocular elongation and thickening of the choroid, which effectively pushes the retina toward the image plane, thereby minimizing the imposed refractive error (Wallman et al., 1995). Conversely, application of negative lenses moves the image plane behind the retina (hyperopic defocus) and results in an increased rate of axial elongation and thinning of the choroid to pull the retina back toward the image plane.

It is well established that visually induced changes in ocular growth are the result of a locally driven ‘retina-to-choroid-to-scleral molecular signaling cascade’ that is initiated by a visual stimulus, followed by biochemical and structural changes in the retina and choroid, ultimately resulting in altered extracellular matrix (ECM) remodeling of the scleral shell (Troilo and Smith, 2019; Tkatchenko et al., 2006; Fischer and Reh, 2000). The choroid, a highly vascularized layer located immediately adjacent to the sclera, has been shown to undergo changes in thickness, permeability, and blood flow during periods of visually guided eye growth (Rada and Palmer, 2007; Fitzgerald et al., 2002; Pendrak et al., 2000; Wallman et al., 1995). Moreover, due to its proximity to the sclera, the choroid is suspected to synthesize and/or release scleral growth regulators to control the rate of ocular elongation in response to visual stimuli (Rada and Palmer, 2007; Marzani and Wallman, 1997). All-trans-retinoic acid is one potential choroidally derived scleral growth regulator, whose choroidal concentrations are modulated by the activity of retinaldehyde dehydrogenase 2 (RALDH2) (Rada et al., 2012; Mertz and Wallman, 2000). Of much interest, therefore, is the identification of genes causally involved in the regulation of the choroidal response during visually guided eye growth.

Here, we report rapid and significant changes in choroidal gene expression of the cytokine, interleukin-6 (IL-6), in response to myopic defocus and in response to chemical compounds known to modulate eye growth. Considering the pleiotropic nature of IL-6 and its involvement in many biological processes, these results suggest that IL-6 may mediate many aspects of the choroidal response in the control of ocular growth.

These studies document, for the first time, that the potent inflammatory cytokine IL-6 is expressed in and released by the choroid during the recovery from FDM. Choroidal upregulation of IL-6 is rapid and transient; significant increases in gene expression were observed after only 90 min of unrestricted vision. IL-6 gene expression reaches a maximum level of expression following 6 hr of recovery, and then begins to decline, returning to control levels by 4 days of recovery. The visual stimulus for choroidal IL-6 gene expression is myopic defocus, as a similar rise in IL-6 is observed after 6 hr of positive (+15 D) lens wear. Finally, nitric oxide appears to directly or indirectly upregulate choroidal IL-6 gene expression. We and others have previously shown that changes in the visual environment can cause rapid changes in ocular growth and refraction as evidenced by changes in scleral proteoglycan synthesis, choroidal retinoic acid synthesis, and choroidal thickness (reviewed in Troilo and Smith, 2019). The chemical mediators that translate visual signals to scleral ECM remodeling to effect changes in eye size have been only partly identified. IL-6 is a multifunctional cytokine synthesized by a variety of cell types that plays key roles in immune responses, inflammatory reactions, as well as the growth and differentiation of many cell types (Kishimoto, 2006). For these reasons, choroidally derived IL-6 could play an important role in the retina-to-sclera signaling cascade. Here, we demonstrate that myopic defocus, as a result of prior form vision deprivation, or due to application of +15 D lenses, stimulates choroidal IL-6 gene expression. In contrast, induction of hyperopic defocus through the application of –15 D lenses resulted in a slight decrease in choroidal IL-6 gene expression, that did not reach statistical significance in the present study.

The observed increase in choroidal IL-6 mRNA was transient; choroidal IL-6 mRNA concentrations peaked at 6 hr following removal of the occluder (myopic defocus), and returned to control levels by 4 days. This transient increase in choroidal IL-6 mRNA is similar to that observed for plasma IL-6 following strenuous exercise (Ostrowski et al., 1998), following ischemic brain injuries (Hagberg et al., 1996; Fassbender et al., 1994), surgical trauma (Nishimoto et al., 1989), and in a subset of patients with multiple sclerosis following treatment with interferon-β (Nakatsuji et al., 2006). It is thought that IL-6 synthesis and release from contracting muscle cells, mononuclear phagocytes, and/or other cell types initiates a cytokine cascade, inducing the expression of other cytokines, such as IL-1 receptor antagonist, to provide a negative feedback loop to reduce the inflammatory response (Jordan et al., 1995). It is unclear as to whether the 6 hr peak in choroidal IL-6 observed in the present study is related to the duration of myopic defocus needed to initiate the maximal IL-6 response, or due to the minimum time required for choroidal IL-6 gene transcription to be upregulated in response to the initial visual stimulus. Our finding of elevated choroidal IL-6 mRNA in treated eyes following only 45 min of myopic defocus together with the previous observation that compensation for positive lenses can occur with as little as 10 min of myopic defocus (Zhu et al., 2005), lead us to favor the latter possibility—that is, a very brief period of myopic defocus would likely stimulate a transient increase in choroidal IL-6 transcription, that reaches a peak 6 hr later.

Choroidal IL-6 gene expression was not significantly affected by rearing chicks in varying light intensities (5–3150 lux), or rearing for 6 hrs in red or blue LED light (58 and 111 lux, respectively), but was significantly lower in choroids from chicks reared in constant darkness for 6 hr, compared with birds reared in any other light conditions examined. It should be noted that the light intensities of the red and blue LED lights used in the present study were relatively low, compared with that of the medium and high intensities of the white LED lights, due to limitations of the maximum light intensity of the red LED lights. It is therefore possible that choroidal IL-6 gene expression might be differentially affected under higher intensity red and blue LED lighting conditions. Wang et al., 2018 previously reported that continuous exposure to blue LED light (435 lux) for 5 days caused a significant hyperopic shift in refraction in both control and form deprived eyes, but had no significant effect on axial length in either control or form deprived eyes (although a trend toward a decrease in axial length was observed in both control and form deprived eyes). Since refraction was significantly affected in blue LED light-reared chicks, but axial length was only minimally affected, we suspect that continual exposure to blue light may have affected other ocular parameters (such as corneal curvature) that would have a significant impact on refraction. We predict that choroidal IL-6 expression is involved in the choroidal and scleral remodeling processes at the posterior pole of the eye that result in changes in vitreous chamber elongation, as opposed to having effects on the anterior segment of the eye. Since IL-6 gene expression was not affected by short-term exposure to red or blue LED light, we predict that exposure to red or blue LED light would have no effect on scleral remodeling, vitreous chamber depth, or axial length, under the conditions used in the present study. Further studies, using higher intensity LED lights, together with additional ocular growth measurements (such as corneal curvature, anterior chamber depth, and lens thickness) are necessary to fully elucidate the role of red and blue LED light on choroidal IL-6 expression, ocular growth, and refraction.

Protein levels of IL-6 were also significantly increased in choroids of recovering eyes following 6 hr of recovery, but were not significantly different following 24 hr of recovery. We suspect that IL‐6 protein is released from choroids and either enters the circulation or adjacent ocular tissues shortly after its synthesis as has been described for IL-6 in skeletal muscle (Steensberg et al., 2000).

Clinical studies have previously suggested an association between inflammation and the progression of myopia. A higher incidence of myopia has been reported among patients with inflammatory diseases such as type 1 diabetes, uveitis, juvenile chronic arthritis, or systemic lupus erythematosus compared to those without inflammatory diseases (Lin et al., 2016; Fledelius et al., 2001; Herbort et al., 2011; Kamath et al., 2013). Herbort et al., 2011 hypothesized that anatomic changes of the eye due to myopia lead to fragility of the choriocapillaris and RPE, predisposing myopic eyes to inflammatory ocular conditions, thereby suggesting that ocular inflammation is a consequence, rather than a cause of myopia. However, our observed elevation in choroidal IL-6 gene and protein expression in response to recovery/myopic defocus does not appear to be due to a general inflammatory response, as other pro-inflammatory cytokines, IFN-γ, and TNF-α, were unaffected by visual manipulations. IL-1B was significantly elevated following 6 hr of recovery, but was unaffected at 1.5 and 3 hr of recovery, suggesting that changes in IL-1B gene expression are downstream to that of IL-6, as has been demonstrated for Il-6 and other plasma cytokines following strenuous exercise (Ostrowski et al., 1999), cancer (Tilg et al., 1994), and infection (Jordan et al., 1995).

The finding that myopic defocus significantly upregulated choroidal IL-6 transcription, but hyperopic defocus had only a modest effect at downregulating choroidal IL-6, may be related to the observation that myopic defocus is a more potent stimulus than hyperopic defocus at causing changes in choroid thickness, with regard to the duration of lens wear needed to elicit changes in choroidal thickness, as well as the duration of the response to lens wear (Zhu et al., 2005). If IL-6 is involved in mediating changes in choroidal thickness, we would predict that myopic defocus-induced increases in choroidal IL-6 gene and protein expression would induce changes in choroidal thickness that would outweigh and outlast the minor reduction in IL-6 expression induced by brief periods of hyperopic defocus.

If choroidal IL-6 gene expression is causally related to ocular changes associated with recovery from myopia, then agents known to block recovery should also block choroidal IL-6 upregulation. To test this, we evaluated choroidal IL-6 gene expression in recovering eyes following intravitreal application of the NOS inhibitor, L-NAME. L-NAME has previously been shown to prevent choroidal thickening and disinhibit scleral proteoglycan synthesis during recovery from induced myopia and in response to positive lens wear (Nickla et al., 2006). We found that intravitreal treatment with L-NAME significantly attenuated the recovery-induced increase in choroidal IL-6 gene expression, indicating that nitric oxide either directly or indirectly regulates choroidal IL-6 gene expression. Treatment of isolated choroids with the NO donor, PAPA-NONOate stimulated IL-6 gene, and protein expression, confirming that choroidal IL-6 is upregulated by NO. NO has been reported to stimulate IL-6 production in skeletal myocytes (Makris et al., 2010), human blood mononuclear cells (Siednienko et al., 2011), and kidney epithelial cells (Demirel et al., 2012) by activating ERK1/2 and p38 MAPK-signaling pathways. We also found that p38 MAPK signaling was crucial for the PAPA-NONOate-mediated activation of IL-6 in chick choroids as incubation with the p38 MAPK inhibitor, SB203580, abolished PAPA-NONOate-stimulation of IL-6 gene expression.

The concentration of retinal dopamine has been implicated in the regulation of eye growth. Daytime levels of retinal dopamine were shown to be reduced in form deprived chick (Stone et al., 1989) and monkey eyes (Iuvone et al., 1989). Furthermore, intravitreal injections of apomorphine (Stone et al., 1989; Iuvone et al., 1991) or dopamine (Gao et al., 2006) prevented the development of deprivation myopia. Interestingly, Nickla et al., 2013 demonstrated that the dopamine agonist, quinpirole, prevented the development of myopia via a nitric oxide-dependent mechanism, indicating that dopamine acts upstream of NO in the signal cascade mediating ocular growth inhibition. In view of our results demonstrating a role for nitric oxide in the regulation of choroidal IL-6 expression, we suspect that dopamine and nitric oxide are located upstream of choroidal IL-6 in the retina-to-scleral signaling cascade.

In the present study, since L-NAME was delivered intravitreally and NO was delivered directly to the choroid (via PAPA-NONOate), it is unclear as to the cellular source of NO generated in response to myopic defocus that is responsible for IL-6 upregulation. NO and nNOS (NOS1) have been detected in virtually all types of retinal neurons, in the RPE, and in several cell types in the chick choroid (Fischer and Stell, 1999; Eldred, 2000). Our finding suggests that treatment of isolated choroids with the NOS substrate, L-arginine, in the presence of 50 mM KCl can similarly upregulate choroidal IL-6 transcription that suggests the endogenous sources of nitric oxide within the choroid have the potential to regulate IL-6 mRNA and protein synthesis. It is also unclear as to the cellular source of choroidal IL-6 in response to myopic defocus. Our immunohistochemical evaluation of IL-6 protein distribution indicated that IL-6 was present as discrete puncta in the RPE, choroidal vascular endothelial cells, and extravascular stromal cells. Any of these cells, as well as myeloid and lymphoid cells, could be the source of visually induced IL-6. However, IL-6-positive choroidal cells identified in the present study may indicate internalization of IL-6 following synthesis and secretion by neighboring cells via a paracrine signaling mechanism, and not necessarily the site of IL-6 synthesis.

Atropine has been shown to prevent experimentally induced myopia in chicks and inhibits myopia development in some children when applied topically (Chia et al., 2012). We therefore evaluated choroidal IL-6 gene expression following in vivo and in vitro treatment with atropine. We found that a single intravitreal injection of atropine to chicks undergoing form deprivation-induced myopia stimulated choroidal IL-6 gene expression. Moreover, incubation of isolated choroids with 0.1% atropine also stimulated choroidal IL-6 gene and protein expression, suggesting that atropine acts directly on the choroid to stimulate IL-6 synthesis.

The results of the present study indicate that choroidal IL-6 is a likely player in the retina-to-sclera signaling cascade underpinning visually guided ocular growth (Figure 10). Of great interest, therefore, are the upstream regulators of choroidal IL-6 gene transcription that relay visual signals, initiated in the retina, to the choroid to bring about changes in IL-6 protein synthesis. IL-6 transcription has been shown to be regulated by a number of factors, including steroid hormones, glucocorticoids, TNF-α, interferon-γ, Il-1b, epidermal growth factor, and amphiregulin (Luo and Zheng, 2016; Bersinger et al., 2011; Lisi et al., 2010 Mahtouk et al., 2005), and some of these mediators have been implicated in myopia development (Dong et al., 2019; Dong et al., 2020; Ding et al., 2018; Gong et al., 2015). Investigations into the retinal and/or RPE expression of these and other factors, known to regulate IL-6 mRNA and protein synthesis, may provide new insights into the visually driven signaling cascade responsible for emmetropization and myopia development.

Figure 10

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Author details

1. Jody A Summers

   Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft

   For correspondence

   jody-summers@ouhsc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8847-7812

2. Elizabeth Martinez

   Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

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