TNF-α in Uveitis: From Bench to Clinic

Abstract

Uveitis is an inflammation of the iris, ciliary body, vitreous, retina, or choroid, which has been shown to be the first manifestation of numerous systemic diseases. Studies about the immunopathogenesis and treatment of uveitis are helpful to comprehend systemic autoimmune diseases, and delay the progression of systemic autoimmune diseases, respectively. Tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, plays a pivotal role in intraocular inflammation based on experimental and clinical data. Evidence of the feasibility of using anti-TNF-α agents for uveitis management has increased. Although there are numerous studies on TNF-α in various autoimmune diseases, the pathological mechanism and research progress of TNF-α in uveitis have not been reviewed. Therefore, the objective of this review is to provide a background on the role of TNF-α in the immunopathogenesis of uveitis, as well as from bench to clinical research progress, to better guide TNF-α-based therapeutics for uveitis.

Regulations of Retinal Inflammation: Focusing on Müller Glia

“…The TNF superfamily, composed of 19 ligands and 29 receptors that are all pro-inflammatory, plays various roles in the body ( Aggarwal et al, 2012 ). TNF-α and its receptors are among the most studied members of this family, especially in retinal inflammation ( Jiang et al, 2021 ). TNF-α primarily exists as a transmembrane protein, which binds and activates TNFR1 and TNFR2, while the TNF-α converting enzyme (also known as ADAM17, which also cleaves TNFRs to produce soluble TNFRs) can cleave the transmembrane TNF-α into a soluble form (sTNF-α), which activates primarily TNFR1 ( Jiang et al, 2021 ).…”

“…TNF-α and its receptors are among the most studied members of this family, especially in retinal inflammation ( Jiang et al, 2021 ). TNF-α primarily exists as a transmembrane protein, which binds and activates TNFR1 and TNFR2, while the TNF-α converting enzyme (also known as ADAM17, which also cleaves TNFRs to produce soluble TNFRs) can cleave the transmembrane TNF-α into a soluble form (sTNF-α), which activates primarily TNFR1 ( Jiang et al, 2021 ). TNF-α expression has been observed in MG and it is highly inducible by stimulations like IL-1β, as discussed above.…”

“…TNFR1 and TNFR2 expression in MG has also been reported, which can be inhibited and result in decreased NF-κB inflammatory responses ( Ji et al, 2022 ), indicating their critical roles in the inflammatory responses. P38MAPK and JNK signaling pathways are also downstream of the TNFR, involving in important cellular functions including cell survival, proliferation and immune defense, ultimately lead to deaths of retinal neuron and vasculopathy ( Jiang et al, 2021 ). Interestingly, mammals and zebrafish react differently to the same factor.…”

Effects of the Chinese Herb Medicine Formula “She-Xiang-Yu-Hong” Ointment on Wound Healing Promotion in Diabetic Mice

“…The current levels of TNF- α and IL-6 were a key factor in the persistent inflammation response in the wound of diabetic patients [ 17 ]. TNF- α , a secreted protein, exhibits numerous cellular functions (e.g., the control of apoptosis, cell differentiation, and cell proliferation as well as cell growth) [ 18 ]. IL-6, a major constituent of the contractile apparatus, is extensively used as a marker of myofibroblast formation [ 19 , 20 ].…”

“…Therefore, CD31 can also indicate the level of angiogenesis. In order to confirm whether SXYH ointment can promote angiogenesis in diabetic patients, we used immunohistochemical staining to detect the expression of the abovementioned three proteins [ 18 ]. As shown in Figure 5 , SXYH ointment increased the positive expression of CD31 and VEGF in newly healed skin tissue by 7 and 14 days compared with the drug-loaded control group.…”