Phospholipase A2 inhibits cisplatin-induced acute kidney injury by modulating regulatory T cells by the CD206 mannose receptor

Abstract

Previously, we found that Foxp3-expressing CD4(+) regulatory T (Treg) cells attenuate cisplatin-induced acute kidney injury in mice and that bee venom and its constituent phospholipase A2 (PLA2) are capable of modulating Treg cells. Here we tested whether PLA2 could inhibit cisplatin-induced acute kidney injury. As a result of treatment with PLA2, the population of Treg cells was significantly increased, both in vivo and in vitro. PLA2-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, and pro-inflammatory cytokine production upon cisplatin administration. These renoprotective effects were abolished by depletion of Treg cells. Furthermore, PLA2 bound to CD206 mannose receptors on dendritic cells, essential for the PLA2-mediated protective effects on renal dysfunction. Interestingly, PLA2 treatment increased the secretion of IL-10 in the kidney from normal mice. Foxp3(+)IL-10(+) cells and CD11c(+)IL-10(+) cells were increased by PLA2 treatment. The anticancer effects of repeated administrations of a low dose of cisplatin were not affected by PLA2 treatment in a tumor-bearing model. Thus, PLA2 may prevent inflammatory responses in cisplatin-induced acute kidney injury by modulating Treg cells and IL-10 through the CD206 mannose receptor.

Protective Effects of Intratracheally-Administered Bee Venom Phospholipase A2 on Ovalbumin-Induced Allergic Asthma in Mice

“…Furthermore, we found that PLA2 is the active compound in bee venom capable for modulating the Treg populations, both in vitro and in vivo [9,10,11]. PLA2 from bee venom belongs to group III secreted PLA2 (sPLA2) enzymes, which play important roles in a wide range of cellular functions, including phospholipid metabolism, signal transduction, and inflammatory and immune responses [27].…”

“…Chung et al have reported that bvPLA2 directly bound to CD206 mannose receptor on dendritic cells and induces the secretion of prostaglandin E2 (PGE2), which promotes immune tolerance through Treg differentiation via PGE2 receptor signaling and prevents the neuroinflammatory responses in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease [9]. In addition, anti-inflammatory effects bvPLA2 was also mediated by IL-10 secretion and Treg activation in cisplatin-induced acute kidney injury model [10]. Based on these results, we supposed that bvPAL2 could inhibit inflammatory responses by modulating Treg cells through the CD206 mannose receptor.…”

“…However, bvPLA2 treatment suppressed the increment, suggesting that bvPLA2 can regulate the PLA2-mediated metabolic pathway in the lung. Moreover, other groups and we have tested whether enzymatic activity of bvPLA2 is necessary for its therapeutic effect using heat- or chemically-inactivated bvPLA2, and found that enzymatic activity of bvPLA2 is necessary [8,9,10]. Further studies to elucidate targets of this bee venom-derived enzyme for inhibiting lung inflammation are needed.…”

“…Bee venom PLA2 (bvPLA2) is one of the major components of bee venom [8]. Our previous studies reported that bvPLA2 directly bound to the CD206 mannose receptor, which promoted immune tolerance through Treg cells modulation and prevented various inflammatory responses, such as neuroinflammation, airway inflammation, and acute kidney injury [9,10,11]. To study the impact of the route of administration on bvPLA2 penetration into the lungs, bvPLA2 was delivered by intratracheal instillation in an OVA-challenged allergic airway inflammation mouse model.…”

Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

“…Several cancers, including ovarian cancer, have demonstrated resistance or reduced sensitivity to cisplatin treatment, leading to decreased time to disease progression, increased likelihood of relapse, and reduced efficacy upon re-treatment during relapse [3,4]; cisplatin itself causes significant health problems, such as nephrotoxicity [5]. Ideally, cisplatin in combination with a drug that diminishes its negative effects while enhancing the therapeutic effects would decrease resistance or relapse while mitigating its negative effects.…”