Sex- and cell-dependent contribution of peripheral high mobility group box 1 and TLR4 in arthritis-induced pain

Abstract

Supplemental Digital Content is Available in the Text. Peripheral high mobility group box 1 promotes joint pain through TLR4 activation in immune cells that is strongly evident in male but not female mice.

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

“…The same study has shown the involvement of TLR9 in the paclitaxel-induced release of TNF and CXCL1 from male, but not female, macrophages [ 96 ]. Similar sex dimorphisms have also been described in the role of TLR4 in pain processing [ 80 , 97 ]. Collectively, activation of RAGE and CXCR4 possibly by macrophage-derived at-HMGB1 may play a major part in CIPN due to paclitaxel.…”

“…TLRs recognize pathogen-associated molecular pattern (PAMP) and DAMP molecules, followed by activation of the MyD88-dependent NF-κB pathway for production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the MyD88-independent IRF pathway for production of interferon [ 12 , 77 ]. Extracellular HMGB1 interacts with membrane receptors including TLR2, a receptor for lipopeptide, TLR4, a receptor for LPS, and TLR5, a receptor for flagellin, leading to the development or aggravation of inflammatory and pain signals ( Figure 1 C) [ 16 , 78 , 79 , 80 ]. HMGB1 binding to nucleic acids penetrates into the cells, and stimulates endosomal TLR9, which is responsible for innate immunity and autoimmunity [ 12 , 15 , 81 , 82 ].…”

“…In 2001, it was reported for the first time that injection of HMGB1 around the sciatic nerve induced mechanical allodynia in rats [ 90 ]. Recently, increasing evidence has unveiled the pro-nociceptive role of HMGB1 in the peripheral tissue and spinal cord [ 16 , 18 , 29 , 80 , 89 ], and demonstrated that endogenous HMGB1 is involved in the pathogenesis of various types of intractable pain [ 11 , 15 ], including inflammatory pain [ 28 , 29 , 80 ], visceral pain [ 19 , 20 , 30 , 32 ], neuropathic pain [ 23 , 31 , 76 , 91 , 92 ], cancer pain [ 33 ], and post-stroke pain [ 34 ]. Endogenous HMGB1 also appears to play a key role in the development of CIPN in rats or mice treated with cancer chemotherapeutics, such as paclitaxel, oxaliplatin, and vincristine, considering the complete prevention of CIPN by inactivation of HMGB1 with HMGB1-nAb or TMα ( Figure 2 and Table 1) [ 8 , 9 , 10 , 11 ].…”

Use of Integrated Optical Clearing and 2-Photon Imaging to Investigate Sex Differences in Neuroimmune Interactions After Peripheral Nerve Injury

“…This remains an integral process of not only pain induction as a protective mechanism, but also a transition to maladaptive chronic pain in some instances (Renthal et al, 2020 ). Discovering the sex-dependent roles of macrophages in tissue injury is paramount as the incidence macrophage-dependent chronic pain in females is lower than in males (Wiesenfeld-Hallin, 2005 ; Agalave et al, 2020 ; Rudjito et al, 2020 ). As such, identifying sex differences in macrophage biology will serve as a foundation for future studies aimed at exploiting immunological regulation in pain and will serve to create a more tailored approach to therapeutics.…”

Bone innervation and vascularization regulated by osteoclasts contribute to refractive pain-related behavior in the collagen antibody-induced arthritis model

“…For this purpose, we used the collagen antibody-induced arthritis (CAIA) model in which mechanical hypersensitivity was previously observed prior to, during, and following the antibody-induced flare of joint inflammation [20][21][22][23][24][25]. Interestingly, signs of bone loss remain several weeks after resolution of inflammation [20], raising the question whether bone erosion contribute to the persistency of hypersensitivity in this model.…”