Retinoic Acid Potentiates Orbital Tissues for Inflammation Through NF-κB and MCP-1

Abstract

The orbit displays unique vulnerability to inflammatory conditions. The most prevalent of these conditions, thyroid eye disease (TED), occurs in up to 50% of patients with Graves' disease (GD). Whereas the pathology of both TED and GD is driven by autoantibodies, it is unclear why symptoms manifest specifically in the orbit. METHODS. We performed retinoic acid treatment on both normal and TED patient-derived orbital fibroblasts (OFs) followed by mRNA and protein isolation, quantitative realtime polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, RNA sequencing, and Western blot analyses. RESULTS. Both normal and TED patient-derived OFs display robust induction of monocyte chemoattractant protein 1 (MCP-1) upon retinoid treatment; TED OFs secrete significantly more MCP-1 than normal OFs. In addition, pretreatment of OFs with thiophenecarboxamide (TPCA-1) inhibits retinoid-induced MCP-1 induction, suggesting an NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)-dependent mechanism. We also found that treatment with cholecalciferol (vitamin D 3) mitigates MCP-1 induction, likely because of competition between retinoic acid receptors (RARs) and vitamin D receptors (VDR) for their common binding partner retinoid nuclear receptors (RXRs). CONCLUSIONS. Retinoids that naturally accumulate in orbital adipose tissue can act on orbital fibroblasts to induce the expression of inflammation-associated genes. These data suggest a potential role for retinoids in sensitizing the orbit to inflammation.

Downregulation of inflammatory erectile dysfunction by Mantisa religiosa egg-cake through NO-cGMP-PKG dependent NF-kB signaling cascade activated by mixture of salt intake

“…Apparently, this study showed that TNF-α inhibition lowered NF-kB expression and MCP-1 was reduced, following the treatment with a protein-rich-cake (10%PMEC) by a factor of 4. Consistent with our finding, Park et al [81] and Unsworth et al [82] reported that MCP-1 activation induced NF-kB expression, while NF-kB inhibition was reported to prevent TNF-α and MCP-1 inflammatory responses in humans. Thus, it is possible that reduced MCP-1 activation by inhibiting NF-kB with down-regulation of TNF-α in rats treated with protein-rich-cake (10% PMEC) by a factor of 4 could account for the delayed progression of IMED.…”

Orbital inflammatory disorders: new knowledge, future challenges

“…A recent article by Unsworth et al [26 ▪▪ ] argues that retinoid byproducts of the visual chromophore, 11-cis-retinal [27], diffuse across the sclera, accumulate in orbital fatty tissue, and cause de novo synthesis and secretion of MCP-1 (also known as CCL2), an important chemoattractant in orbital inflammatory conditions [28–32]. Indeed, it has long been known that orbital fat is enriched in retinoids [33], and Unsworth et al [26 ▪▪ ] take it a step further by demonstrating that retinoids can diffuse across the sclera in an in-vitro model.…”

“…A recent article by Unsworth et al [26 ▪▪ ] argues that retinoid byproducts of the visual chromophore, 11-cis-retinal [27], diffuse across the sclera, accumulate in orbital fatty tissue, and cause de novo synthesis and secretion of MCP-1 (also known as CCL2), an important chemoattractant in orbital inflammatory conditions [28–32]. Indeed, it has long been known that orbital fat is enriched in retinoids [33], and Unsworth et al [26 ▪▪ ] take it a step further by demonstrating that retinoids can diffuse across the sclera in an in-vitro model. Retinoids that accumulate in orbital tissues outside the eye will be henceforth referred to as ‘tissue retinoids.’ The mechanism of action by retinoids involves the role of retinoids as regulators of transcription through binding to retinoic acid receptors (RAR) and retinoid X receptor (RXR) [34–40].…”

“…A natural competitor for RAR activity is VDR, and vitamin D deficiency is associated with autoimmune inflammatory conditions, such as multiple sclerosis and TED [41,42,43 ▪ ,44]. In the lab, vitamin D appears to compete with RAR and prevent the synthesis of MCP-1 [26 ▪▪ ]. Retinoid analogs may ultimately play a therapeutic role in reducing or preventing secondary orbital inflammation [34,35,38].…”

“…Vitamin D also has a known role in immune system regulation, particularly in multiple sclerosis [42,44,98]. Importantly, Unsworth et al [26 ▪▪ ] have demonstrated in laboratory experiments that vitamin D can reduce cytokine expression by orbital fibroblasts treated with retinoic acid, providing a mechanistic explanation for the role of vitamin D in regulating inflammatory orbitopathy.…”