Cathepsin S as a potential therapeutic target for chronic pain

Montague-Cardoso, Karli; Malcangio, Marzia

doi:10.1016/j.medidd.2020.100047

Cited by 10 publications

(6 citation statements)

References 50 publications

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“…Like most cathepsins, CatS is a small and monomeric endopeptidase ( 61 ). It is synthesized as an inactive zymogen in the lysosomal compartment ( 62 ).…”

Section: Introductionmentioning

confidence: 99%

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

Silva

Malcangio

2021

Front. Pain Res.

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Injuries to the nervous system can result in a debilitating neuropathic pain state that is often resistant to treatment with available analgesics, which are commonly associated with several side-effects. Growing pre-clinical and clinical evidence over the last two decades indicates that immune cell-mediated mechanisms both in the periphery and in the Central Nervous System (CNS) play significant roles in the establishment and maintenance of neuropathic pain. Specifically, following peripheral nerve injury, microglia, which are CNS resident immune cells, respond to the activity of the first pain synapse in the dorsal horn of spinal cord and also to neuronal activity in higher centres in the brain. This microglial response leads to the production and release of several proinflammatory mediators which contribute to neuronal sensitisation under neuropathic pain states. In this review, we collect evidence demonstrating the critical role played by the Fractalkine/CX3CR1 signalling pathway in neuron-to-microglia communication in neuropathic pain states and explore how strategies that include components of this pathway offer opportunities for innovative targets for neuropathic pain.

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“…Like most cathepsins, CatS is a small and monomeric endopeptidase ( 61 ). It is synthesized as an inactive zymogen in the lysosomal compartment ( 62 ).…”

Section: Introductionmentioning

confidence: 99%

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

Silva

Malcangio

2021

Front. Pain Res.

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“…Interestingly, one of the top 20 genes in this module was Gm2a , a gene encoding a co-factor of lysosomal enzymes. Further, two cathepsins ( Ctss and Ctsh ) with relevance to pain (36) were in the top 20 gene list in turquoise . These proteins are enriched in actively phagocytic cells, have lysosomal activity, and modify neuronal spine density extracellularly.…”

Section: Resultsmentioning

confidence: 99%

Newly repopulated spinal cord microglia exhibit a unique transcriptome and correlate with pain resolution

Donovan

Bridges

Nippert

et al. 2022

Preprint

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Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible genetic microglial depletion strategy at both the acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain after transient microglial depletion at the acute-to-chronic phase, which coincided with the timeframe of full repopulation of microglia. These repopulated microglia were morphologically distinct from control microglia, suggesting they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene co-expression network analysis (WGCNA). We intersected these genes with a newly-generated single nuclei microglial dataset from human dorsal horn spinal cord to identify human-relevant genes that may promote homeostatic features of microglia and ultimately promote pain resolution after injury.

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“…Indeed, recent reviews on the topic of FKN and chronic pain discuss the advantages of using a non-promiscuous axis as a specific therapeutic target, supported by convincing preclinical evidence of the axis' role in animal models of pain. The preclinical data encourages the exploration of clinical conditions in patients, to support the axis' translation into clinical benefits ( 65 , 66 ).…”

Section: Direct Evidence Of Chemokines In Trigeminal Painmentioning

confidence: 99%

Chemokines and Pain in the Trigeminal System

2021

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Chemotactic cytokines or chemokines are a large family of secreted proteins able to induce chemotaxis. Chemokines are categorized according to their primary amino acid sequence, and in particular their cysteine residues that form disulphide bonds to maintain the structure: CC, CXC, CX3C, and XC, in which X represents variable amino acids. Among their many roles, chemokines are known to be key players in pain modulation in the peripheral and central nervous systems. Thus, they are promising candidates for novel therapeutics that could replace current, often ineffective treatments. The spinal and trigeminal systems are intrinsically different beyond their anatomical location, and it has been suggested that there are also differences in their sensory mechanisms. Hence, understanding the different mechanisms involved in pain modulation for each system could aid in developing appropriate pharmacological alternatives. Here, we aim to describe the current landscape of chemokines that have been studied specifically with regard to trigeminal pain. Searching PubMed and Google Scholar, we identified 30 reports describing chemokines in animal models of trigeminal pain, and 15 reports describing chemokines involved in human pain associated with the trigeminal system. This review highlights the chemokines studied to date at different levels of the trigeminal system, their cellular localization and, where available, their role in a variety of animal pain models.

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Cathepsin S as a potential therapeutic target for chronic pain

Cited by 10 publications

References 50 publications

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

Newly repopulated spinal cord microglia exhibit a unique transcriptome and correlate with pain resolution

Chemokines and Pain in the Trigeminal System

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