Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice

Abstract

Oxidation products of the naturally occurring phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), which are known as OxPAPC, accumulate in atherosclerotic lesions and at other sites of inflammation in conditions such as septic inflammation and acute lung injury to exert pro- or anti-inflammatory effects. It is currently unknown whether OxPAPC also contributes to inflammatory pain and peripheral neuronal excitability in these conditions. Here, we observed that OxPAPC dose-dependently and selectively activated human TRPA1 nociceptive ion channels expressed in HEK293 cells in vitro, without any effect on other TRP channels, including TRPV1, TRPV4 and TRPM8. OxPAPC agonist activity was dependent on essential cysteine and lysine residues within the N-terminus of the TRPA1 channel protein. OxPAPC activated calcium influx into a subset of mouse sensory neurons which were also sensitive to the TRPA1 agonist mustard oil. Neuronal OxPAPC responses were largely abolished in neurons isolated from TRPA1-deficient mice. Intraplantar injection of OxPAPC into the mouse hind paw induced acute pain and persistent mechanical hyperalgesia and this effect was attenuated by the TRPA1 inhibitor, HC-030031. More importantly, we found levels of OxPAPC to be significantly increased in inflamed tissue in a mouse model of chronic inflammatory pain, identified by the binding of an OxPAPC-specific antibody. These findings suggest that TRPA1 is a molecular target for OxPAPC and OxPAPC may contribute to chronic inflammatory pain through TRPA1 activation. Targeting against OxPAPC and TRPA1 signaling pathway may be promising in inflammatory pain treatment.

TRPA1: Acrolein meets its target

“…These conditions are often associated with an increased endogenous aldehyde load. Endogenous unsaturated aldehydes such as 4-hydroxynonenal (4-HNE), often contained within oxidized phospholipids and associated with asthma, and methylglyoxal, associated with diabetes, were identified as TRPA1 agonists, suggesting that chronic activity of TRPA1 may contribute to the disease etiology of these conditions (Trevisani et al, 2007; Ohkawara et al, 2012; Liu et al, 2016). …”

Antinociception by the anti‐oxidized phospholipid antibody E06

“…Recently, we and others have shown that OxPL including oxidized 1‐palmitoyl‐2‐arachidonoyl‐sn‐glycero‐3‐phosphocholine (OxPAPC) activate heterologous and native TRPA1 as well as TRPV1 channels in vitro . Once locally injected, these lipids elicit thermal and mechanical hypersensitivity as well as acute nociception in vivo (Patwardhan et al ., ; Liu et al ., ; Oehler et al ., ). Furthermore, we showed that OxPAPC‐mediated activation of TRPA1 channels in vitro , as well as thermal and mechanical hypersensitivity induced by OxPAPC in vivo are blocked by a function‐blocking autoantibody against oxidized phosphatidylcholine (OxPC), the E06 monoclonal antibody (Oehler et al ., ).…”

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

“…Nrf2 in macrophages was shown to exert direct anti-inflammatory effects[83] and an anti-inflammatory, reparative function in the brain was ascribed to Mox macrophages detected in microglia after stimulation of nicotinic receptors[84]. Of note, a recent report demonstrated regulation of chronic inflammatory pain by OxPAPC in neurons via activation of TRPA1 channels[85]. …”