Advanced Glycation End Products and Activation of Toll-like Receptor-2 and -4 Induced Changes in Aquaporin-3 Expression in Mouse Keratinocytes

Abstract

Prolonged inflammation and impaired re-epithelization are major contributing factors to chronic non-healing diabetic wounds; diabetes is also characterized by xerosis. Advanced glycation end products (AGEs), and the activation of toll-like receptors (TLRs), can trigger inflammatory responses. Aquaporin-3 (AQP3) plays essential roles in keratinocyte function and skin wound re-epithelialization/re-generation and hydration. Suberanilohydroxamic acid (SAHA), a histone deacetylase inhibitor, mimics the increased acetylation observed in diabetes. We investigated the effects of TLR2/TLR4 activators and AGEs on keratinocyte AQP3 expression in the presence and absence of SAHA. Primary mouse keratinocytes were treated with or without TLR2 agonist Pam3Cys-Ser-(Lys)4 (PAM), TLR4 agonist lipopolysaccharide (LPS), or AGEs, with or without SAHA. We found that (1) PAM and LPS significantly upregulated AQP3 protein basally (without SAHA) and PAM downregulated AQP3 protein with SAHA; and (2) AGEs (100 µg/mL) increased AQP3 protein expression basally and decreased AQP3 levels with SAHA. PAM and AGEs produced similar changes in AQP3 expression, suggesting a common pathway or potential crosstalk between TLR2 and AGEs signaling. Our findings suggest that TLR2 activation and AGEs may be beneficial for wound healing and skin hydration under normal conditions via AQP3 upregulation, but that these pathways are likely deleterious in diabetes chronically through decreased AQP3 expression.

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…Skin disorders are often evident in T1DM, usually in association with heightened levels of advanced glycation end-products (AGEs) [193]. As AGEs act via the AGE receptor, RAGE, to increase NF-kB and pro-inflammatory signaling in the skin as in other body sites [194], the attenuated capacity to upregulate the mitochondrial melatonergic pathway in the T1DM skin will be important to determine. Skin disorders are common in other 'autoimmune'/'immune-mediated' disorders, including multiple sclerosis [195] and Parkinson's disease [196].…”

Phosphatidylglycerol to Treat Chronic Skin Wounds in Diabetes

“…This result suggests that some molecules, such as AGEs, which accumulate during diabetes, may underlie the reduction in AQP3 rather than the high blood glucose levels per se. Indeed, AGEs have been found to decrease AQP3 protein expression in mouse keratinocytes under certain conditions [ 79 ]. A role for AQP3 in the impaired wound healing of aged skin is also suggested by results showing that AQP3 levels are decreased in both extrinsically (sun-exposed) and intrinsically (chronologically) aged human skin [ 76 , 77 ] and in mouse skin [ 75 ].…”

The Role of Toll-like Receptors (TLRs) and Their Related Signaling Pathways in Viral Infection and Inflammation

“…Furthermore, the role of immunoregulatory and antiviral oligonucleotides is addressed [ 4 ]. The six experimental research papers cover topics ranging from TLR2 and TLR4 polymorphisms and susceptibility to bacterial sepsis [ 5 ]; decrease in endotoxin-induced activation of TLR4 signaling by xanthohumol-rich hop extract [ 6 ], advanced glycosylation end-products and TLR- induced changes in aquaporin-3 expression in mouse keratinocytes [ 7 ]; TLR4 signaling in periodontal ligament cells in response to mechanical compression [ 8 ]; identification of optimal TLR8 ligand by altering the position of 2′-O-ribose methylation [ 9 ]; to a breast cancer vaccine containing a novel TLR7 agonist showing antitumor effects [ 10 ].…”

“…The effects of TLR2/TLR4 activators and AGEs on keratinocyte AQP3 expression in the presence and absence of SAHA was studied in primary mouse keratinocytes. The results indicate that TLR2 activation and AGEs may be beneficial for wound healing and skin hydration under normal conditions via AQP3 upregulation, but these pathways are likely deleterious in diabetes [ 7 ].…”