Increased Expression of TLR4 in Circulating CD4+T Cells in Patients with Allergic Conjunctivitis and In Vitro Attenuation of Th2 Inflammatory Response by Alpha-MSH

Abstract

Ocular allergic diseases are frequently seen in ophthalmological clinical practice. Immunological damage is mediated by a local Th2 inflammatory microenvironment, accompanied by changes in circulating cell subsets, with more effector cells and fewer T regulatory cells (Tregs). This study aimed to evaluate the involvement of toll-like receptor 4 (TLR4) and α-melanocyte stimulating hormone (α-MSH) in the immune regulation associated with perennial allergic conjunctivitis (PAC). We performed an Ag-specific stimulation during 72 h of culturing with or without lipopolysaccharide (LPS) or α-MSH in peripheral blood mononuclear cells (PBMC), analyzing the cell subsets and cytokines induced by the stimuli. We also determined α-MSH in tear samples from healthy donors (HD) or PAC patients. Our findings demonstrate an immunological dysregulation characterized by an increased frequency of CD4+TLR4+ in the PBMC of patients with PAC, compared to HD. Most of these CD4+TLR4+ cells were also CD25+, and when α-MSH was added to the culture, the percentage of CD4+CD25+FoxP3+ increased significantly, while the percentage of CD69+ cells and cytokines IL-4 and IL-6 were significantly decreased. In tears, we found an increased concentration of α-MSH in PAC patients, compared with HD. These findings indicate a novel mechanism involved in controlling ocular allergic diseases, in which α-MSH diminishes the concentration of IL-6 and IL-4, restoring the frequency of Tregs and down-regulating CD4 activation. Moreover, we demonstrated the involvement of CD4+TLR4+ cells as an effector cell subset in ocular allergy.

Effects of rAmb a 1-Loaded PLGA-PEG Nanoparticles in a Murine Model of Allergic Conjunctivitis

“…This therapeutic effect is mainly due to the increase in the Th1/Th2 ratio, the change in IgE and IgG2a antibody levels, and the reduction in mast-cell degranulation. In addition to the increase in the Th1/Th2 ratio, the increase in regulatory T cells (Tregs) and the epigenetic changes in T cells will also influence the effect of allergen-specific immunotherapy [ 30 ]. In order to understand the mechanism more deeply, it is necessary to further confirm the effect of allergen-loaded PLGA-PEG nanoparticles on effector T cells, Tregs, and epigenetic changes in T cells [ 31 , 32 ].…”

Therapeutic Effects of Stimulating the Melanocortin Pathway in Regulating Ocular Inflammation and Cell Death

“…It has been shown that regulatory T cells can be generated in vitro by treating antigen-stimulated CD4 + T cells with a supplementation of α-MSH at the physiological concentration of 10 −11 M. The α-MSH-induced Tregs express CD25 and produce TGF-β, but not IL-4 [29,31,32]. In a recent study, α-MSH was also found in tears, and its concentration increased in perennial allergic conjunctivitis (PAC) patients compared with healthy participants [33].…”

Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player

“…α-MSH is composed of 13 amino acids and is best known for its pigmentary effects in skin [ 28 ], but also has been indicated to exert anti-inflammatory and microbicidal effects discussed below [ 29 , 30 , 31 , 32 , 33 , 34 ].…”