Proanthocyanidins: A novel approach to Henoch‑Schonlein purpura through balancing immunity and arresting oxidative stress via TLR4/MyD88/NF‑κB signaling pathway (Review)

Abstract

Henoch-Schonlein purpura (HSP), a recurrent and immunoglobulin (Ig)A-mediated vasculitis, presents not only as skin lesions but also as systemic involvement that can be life-threatening. Although the etiology of HSP remains unknown, immune imbalance and oxidative stress (OS) are primary contributors to its pathogenesis, alongside the abnormal activation of Toll-like receptor (TLR)/myeloid differentiation primary response gene 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. TLRs, especially TLR4, stimulate downstream signaling molecules such as NF-κB and proinflammatory cytokines, which are released when TLRs combine with the key adapter molecule MyD88. This leads to the activation of T helper (Th) cell 2/Th17 and overproduction of reactive oxygen species (ROS). The function of regulatory T (Treg) cells is suppressed in the process. Th17/Treg imbalance then produces various inflammatory cytokines to promote proliferation and differentiation of B cells and the secretion of antibodies. IgA is secreted, and it binds to vascular endothelial surface receptors where the complex induces injury of the vascular endothelial cells. Additionally, excessive ROS creates OS that leads to an inflammatory response and vascular cell apoptosis or necrosis, thereby contributing to vascular endothelial damage and HSP occurrence. Proanthocyanidins are active compounds naturally enriched in fruits, vegetables and plants. Proanthocyanidins have diverse properties, including anti-inflammatory, antioxidant, antibacterial, immunoregulatory, anticarcinogenic and vascular protective effects. Proanthocyanidins are used in the management of various diseases. Proanthocyanidins regulate T cells, equilibrate immunity and arrest OS by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Considering the pathogenesis of HSP and the properties of proanthocyanidins, the present study hypothesized that these compounds may potentially lead to HSP recovery through modulating the immune equilibrium and preventing OS by inhibiting the TLR4/MyD88/NF-κB pathway. To the best of our knowledge, however, little is known about the positive effects of proanthocyanidins against HSP. The present review summarizes the potential of proanthocyanidins to treat HSP.

Keywords: Henoch-Schonlein purpura; immune imbalance; oxidative stress; proanthocyanidin.

Figure 1

The possible pathogenesis of HSP. PAMPs are specifically recognized by TLRs. By binding to MyD88, activated TLR4 stimulates the downstream signaling molecule NF-κB to trigger signal transduction cascades and activate immune cells. Th1/Th2 imbalance and overactivated Th17 release inflammatory cytokines and also accelerate the proliferation and differentiation of B cells, which secrete antibodies. IgA may combine with VEC surface receptors to produce IL-8 and LTB4, which recruit neutrophils to the blood vessel wall and promote OS and inflammation due to downregulation of superoxide dismutase, total antioxidant capacity, glutathione and heme oxygenase-1 and the upregulation of reactive oxygen species, malondialdehyde, nitric oxide and inflammatory factors. These alterations leads to VEC damage, an increase in vascular permeability and IgA being deposited on the vascular wall, thereby contributing to the occurrence and progression of HSP. HSP, Henoch-Schonlein purpura; OS, oxidative stress; TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κ-B; Th, T helper; IL, interleukin; TNF-α, tumor necrosis factor-α; Ig, immunoglobulin; LTB4, leukotriene B4; VEC, vascular endothelial cell; PAMP, pathogen-associated molecular pattern; Treg, regulatry T cell; ⊕, activation; ↔, binding; ↑↑, upregulation; ↓↓, downregulation.

Figure 2

Proanthocyanidins structure, properties and application. Proanthocyanidins, a type of polyphenolic compound, are widespread in fruits and plants, such as grapes, cranberry, black currant, pomegranate, cocoa and medlar. Proanthocyanidins possess antioxidation, immunomodulation and anti-inflammation effects and are used in numerous disorders (such as OS-associated diseases inflammatory disorders, cardiovascular dysfunction and diabetes). Mechanism of action involves inhibiting OS (decreasing ROS and MDA and increasing SOD, GSH and catalase), reducing inflammatory responses (inhibiting IL-17, IL-6, IL-21, IL-22 and TNF-α) and balancing immunity (reducing Th2, Th17 and B cells and increasing Treg cells) via the suppression of the TLR4/MyD88/NF-κB signaling pathway. OS, oxidative stress; ROS, reactive oxygen species; MDA, malondialdehyde; TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κ-B; Th, T helper; IL, interleukin; TNF-α, tumor necrosis factor-α; SOD, superoxide dismutase; GSH, glutathione; Ɵ, suppression; ↑↑, upregulation; ↓↓, downregulation.

Figure 3

Potential mechanisms of proanthocyanidins in treatment of HSP. Proanthocyanidins inhibit TLR4/MyD88/NF-κB signaling to arrest OS by eliminating oxidants such as ROS, MDA and NO, accompanied by an increase of antioxidants, such as HO-1, SOD and GSH. By inhibiting the TLR4/MyD88/NF-κB pathway, proanthocyanidins cause a decrease in Th2/Th17 cells and an increase in the Treg cells, which inhibits release of inflammatory factors (IL-1, IL-6, IL-4, IL-6, IL-17, IL-21, LTB4 and TNF-α), activation of B cells and antibody production, facilitating immune homeostasis. The aforementioned alterations improve the vascular endothelial function and vessel integrity, thereby potentially contributing to control of HSP. HSP, Henoch-Schonlein purpura; TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κ-B; OS, oxidative stress; ROS, reactive oxygen species; MDA, malondialdehyde; NO, nitric oxide; HO-1, heme oxygenase-1; SOD, superoxide dismutase; GSH, glutathione; Th, T helper; Treg, regulatory T cell; IL, interleukin; TNF-α, tumor necrosis factor-α; Ig, immunoglobulin; Ɵ, suppression; ⊕, improvement; ↑↑, upregulation; ↓↓, downregulation.

Figure 4

Establishment of HSP-like rat models. (A) Cutaneous eruption on the tail of a HSP-like mouse model demonstrating a typical purpura-like lesions on the skin. (B) Histopathological changes of skin of HSP-like rat models revealing leukocytoclastic vasculitis accompanied by edema in dermis and fibrinoid degeneration on the vascular walls in the upper dermal layer. (C) Histopathological alterations of the kidney of a HSP-like mouse model revealing proliferation of mesangial cells/stroma with protein exudation and scattered hemorrhage in renal tissue. (D) Immunofluorescence of the kidney of the HSP-like mouse model revealing granular deposition of IgA. HSP, Henoch-Schonlein purpura.