Abstract
Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.
Highlights
Chronic diseases, including neuropathic pain of various origins, are still scarcely managed in the clinic
This study shows a possible mechanism of action of N-palmitoyl-D-glucosamine (PGA), a lipid molecule featuring a C-16 saturated alkyl chain bound through an amide bond to a D-glucose unit, by the direct binding to the MD2/toll-like receptor 4 (TLR4) receptor complex
Resembles other TLR4 ligands based on a glucosamine core and linear carbon chains [56,57], and is produced by bacteria whose function is to facilitate the growth of other organisms or to promote mutual well-being between the host and its gut microbiome [13]
Summary
Chronic diseases, including neuropathic pain of various origins, are still scarcely managed in the clinic. The mechanisms at the basis of neuropsychiatric symptoms associated with chronic pain are still poorly understood. Extensive evidence highlighted the role of inflammatory or immune system pathways in chronic pathologies including neuropathic pain [1,2]. A critical role for proinflammatory mediators, as cytokines and chemokines from neurons and non-neuronal cells, together with a possible peripheral immune cells interaction, has been suggested in neuropathic pain pathophysiology [3,4]. TLR4 is able to bind the molecular patterns associated with pathogens (PAMPs), and recognizes lipopolysaccharide (LPS) derived from gram-negative bacteria (including those of the gut microbiota), as well as molecules of endogenous origin produced by cellular damage (DAMPs) [5]
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