TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. High hydrogen ion concentration (acidosis) found in synovial fluid in RA patients is associated with disease severity. Acidosis signaling acting on proton-sensing receptors may contribute to inflammation and pain. Previous studies focused on the early phase of arthritis (<5 weeks) and used different arthritis models, so elucidating the roles of different proton-sensing receptors in the chronic phase of arthritis is difficult. We intra-articularly injected complete Freund’s adjuvant into mice once a week for 4 weeks to establish chronic RA pain. Mice with knockout of acid-sensing ion channel 3 (ASIC3) or transient receptor potential/vanilloid receptor subtype 1 (TRPV1) showed attenuated chronic phase (>6 weeks) of RA pain. Mice with T-cell death-associated gene 8 (TDAG8) knockout showed attenuated acute and chronic phases of RA pain. TDAG8 likely participates in the initiation of RA pain, but all three genes, TDAG8, TRPV1, and ASIC3, are essential to establish hyperalgesic priming to regulate the chronic phase of RA pain.

TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain

“…TDAG8 gene-deficient mice show reduced number of Th17 cells and secretion of IL-17A [18]. Consistent with these data, RA disease severity and RA-evoked pain were attenuated in TDAG8 gene-deficient mice in the RA mouse model [19]. However, how TDAG8 regulates RA and RA-evoked pain in the early and late pain phases remains unclear.…”

Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner

“…CFA evokes both acute (within 18-h) and chronic (>6 weeks) inflammatory pain ( Hsieh et al, 2017 ; Keeble et al, 2005 ), as demonstrated by altered evoked-pain behaviors, such as hot/cold plate tests. However, such evoked-pain tests are neither ethologically relevant to rodents, nor model experience of human chronic pain ( Rice et al, 2008 ).…”

“…There is conflicting evidence surrounding the role of ASICs in inflammatory pain, some studies showing no change, others decreased pain and still others increased pain ( Price et al, 2001 ; Sluka et al, 2003 ). In terms of joint inflammation, ASIC3 −/− , TDAG8 −/− (a proton-sensing GPCR) and TRPV1 −/− mice showed decreased hyperalgesia in an ankle inflammation model ( Hsieh et al, 2017 ). In addition, Ikeuchi et al (2009) observed upregulation of ASIC3 immunoreactivity in knee-innervating DRG neurons after carrageenan-induced acute knee inflammation in mice.…”

“…Joint acidosis correlates with increased severity of inflammatory arthritis in humans, and acidic solutions activate and sensitize rodent nociceptors ( Farr et al, 1985 ; Smith et al, 2011 ). Mice lacking the proton-gated ion channels acid-sensing ion channel 3 (ASIC3) and TRPV1 have reduced mechanical hyperalgesia following intra-articular CFA injection ( Hsieh et al, 2017 ), but not following subcutaneous hind paw CFA injection, suggesting regional differences in pain processing ( Staniland and McMahon, 2009 ). Subsequently, using magnetic resonance spectroscopic imaging, we found no evidence of tissue acidosis following subcutaneous CFA injection ( Wright et al, 2018 ), suggesting absence of a key stimulus for ASIC3/TRPV1 activation, hence perhaps explaining the lack of phenotype observed in the hind paw CFA model.…”

Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

“…In a mouse model of fibromyalgia, Asic3 −/− mice failed to develop chronic widespread muscle pain induced by repeated intramuscular injections of acid saline [ 60 – 62 ]. Also, Asic3 −/− mice show impaired triggering of pain associated with tissue acidosis under the conditions of surgery, cardiac ischemia, muscle and joint inflammation, and rheumatoid arthritis [ 42 , 54 , 63 – 67 ]. In mechano-sensing, Asic3 −/− mice show abnormal neurosensory mechanotransduction of cutaneous and visceral afferents in ex vivo studies of electrophysiological recordings on tissue-nerve preparations [ 4 ].…”