Lysophosphatidylcholine 16:0 mediates chronic joint pain associated to rheumatic diseases through acid-sensing ion channel 3

Abstract

Supplemental Digital Content is Available in the Text.A combination of clinical and preclinical data that support a role for the lysolipid LPC16:0 via acid-sensing ion channels 3 in chronic joint pain related to rheumatic diseases.

Potentiation of ASIC currents by lysophosphatidic acid in rat dorsal root ganglion neurons

“…LPC activates ASIC3 channels at pH 7.4 and potentiates its acid‐induced activity (Marra et al, 2016). Recently, the same research group has reported a role for LPC16:0 via ASIC3 channels in chronic pain arising from joints (Jacquot et al, 2022). However, we observed that no detectable current was recorded following application of LPA (range from 0.1 to 10 μM) at physiological pH 7.4, suggesting no activation of any ion channels including ASICs.…”

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

“…They are activated by a fast-extracellular acidosis from conditioning physiological pH to acidic test pH and inactivated by sustained extracellular acidosis. Interestingly, rat and human ASIC3 channels can be also activated at neutral (7.4) pH by lipids (arachidonic acid and lysophosphatidylcholine) [ 20 , 21 ] and hASIC3a channels have been shown to be sensitive to both acidic and alkaline pH [ 22 ].…”

“…Regarding joint pain , ASIC3 was found to be expressed in more than 30% of DRG neurons innervating the knee joint in mice [ 227 ], and ASIC expression in DRG is increased in mice models of acute arthritis or rheumatoid arthritis [ 227 , 228 ]. LPC and arachidonic acid (AA) were shown to induce a slow constitutive activation of ASIC3 including the human isoform [ 21 ], and high levels of lysophosphatidylcholine (LPC) were measured in synovial fluids of two independent cohorts of patients with rheumatic diseases, correlated with pain outcomes in the cohort of osteaoarthritis (OA) patients [ 20 ]. LPC also evokes a robust depolarizing current in DRG neurons at physiological pH 7.4, increases the firing of spinal nociceptive neuron innervated by nociceptive C-fiber, and induces pain behavior in rats and mice after subcutaneous co-injection with arachidonic acid, effects that are significantly reduced by ASIC3 blockers, including APETx2, or in ASIC3 knockout mice [ 20 , 21 , 229 ].…”

“…LPC and arachidonic acid (AA) were shown to induce a slow constitutive activation of ASIC3 including the human isoform [ 21 ], and high levels of lysophosphatidylcholine (LPC) were measured in synovial fluids of two independent cohorts of patients with rheumatic diseases, correlated with pain outcomes in the cohort of osteaoarthritis (OA) patients [ 20 ]. LPC also evokes a robust depolarizing current in DRG neurons at physiological pH 7.4, increases the firing of spinal nociceptive neuron innervated by nociceptive C-fiber, and induces pain behavior in rats and mice after subcutaneous co-injection with arachidonic acid, effects that are significantly reduced by ASIC3 blockers, including APETx2, or in ASIC3 knockout mice [ 20 , 21 , 229 ]. In a pathology-derived mouse model, intra-articular injections of LPC trigger a chronic pain state associated with anxiety-like behaviors that involves ASIC3-containing channels and is significantly reduced by intra-articular APETx2 [ 20 ].…”

“…LPC also evokes a robust depolarizing current in DRG neurons at physiological pH 7.4, increases the firing of spinal nociceptive neuron innervated by nociceptive C-fiber, and induces pain behavior in rats and mice after subcutaneous co-injection with arachidonic acid, effects that are significantly reduced by ASIC3 blockers, including APETx2, or in ASIC3 knockout mice [ 20 , 21 , 229 ]. In a pathology-derived mouse model, intra-articular injections of LPC trigger a chronic pain state associated with anxiety-like behaviors that involves ASIC3-containing channels and is significantly reduced by intra-articular APETx2 [ 20 ]. APETx2 was also shown to reduce pain progression when injected in the early phase of an OA rat model [ 154 ].…”