Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity

Agalave, Nilesh M.; Rudjito, Resti; Farinotti, Alex Bersellini; Khoonsari, Payam Emami; Sándor, Katalin; Nomura, Yuki; Szabo-Pardi, Thomas A.; Urbina, Carlos Morado; Palada, Vinko; Price, Theodore J.; Harris, Helena Erlandsson; Burton, Michael D.; Kultima, Kim; Svensson, Camilla I.

doi:10.1097/j.pain.0000000000002033

Cited by 44 publications

(25 citation statements)

References 67 publications

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“…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.…”

Section: Role Of Hmgb1 In Cipnsupporting

confidence: 67%

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

Sekiguchi

Kawabata

2020

IJMS

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Chemotherapy-induced peripheral neuropathy (CIPN), one of major dose-limiting side effects of first-line chemotherapeutic agents such as paclitaxel, oxaliplatin, vincristine, and bortezomib is resistant to most of existing medicines. The molecular mechanisms of CIPN have not been fully understood. High mobility group box 1 (HMGB1), a nuclear protein, is a damage-associated molecular pattern protein now considered to function as a pro-nociceptive mediator once released to the extracellular space. Most interestingly, HMGB1 plays a key role in the development of CIPN. Soluble thrombomodulin (TMα), known to degrade HMGB1 in a thrombin-dependent manner, prevents CIPN in rodents treated with paclitaxel, oxaliplatin, or vincristine and in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy. In this review, we describe the role of HMGB1 and its upstream/downstream mechanisms in the development of CIPN and show drug candidates that inhibit the HMGB1 pathway, possibly useful for prevention of CIPN.

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Section: Role Of Hmgb1 In Cipnsupporting

confidence: 67%

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

Sekiguchi

Kawabata

2020

IJMS

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“…In support of the latter, male microglia exhibited an enrichment of the RAGE receptor binding Gene Ontology term relative to female microglia isolated from cortical tissues [ 91 ]. Furthermore, recent work indicated sex-dependent actions of HMGB1, a known RAGE ligand, on spinal cord microglia in a model of hypersensitivity [ 92 ]. Additionally, recent work indicated unexplained sex-dependent effects of FPS-ZM1 treatment on several measures of progression in SOD1 G93A mice [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

MacLean

Juranek

Cuddapah

et al. 2021

J Neuroinflammation

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Background Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. Methods We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. Results Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. Conclusions Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

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“…There are also potential sex differences in the impact of pain on functioning in daily life, and in the success of specific coping strategies [ 35 ]. In addition to differences in prevalence between the sexes, sex differences in underlying pain mechanisms and their modulation by immune cells have been recently reported [ 36 – 38 ], and immune responses in general can differ by sex [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank

et al. 2021

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Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.

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Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity

Abstract: Supplemental Digital Content is Available in the Text. Disulfide high mobility group box 1 protein activates microglia and induces pain-like behavior in male and female mice, but the mechanisms underlying its central pronociceptive effects are sex-dependent.

Cited by 44 publications

References 67 publications

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank

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