Autoimmune regulation of chronic pain

Lacagnina, Michael J.; Heijnen, Cobi J.; Watkins, Linda R.; Grace, Peter M.

doi:10.1097/pr9.0000000000000905

Cited by 34 publications

(24 citation statements)

References 186 publications

(160 reference statements)

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“…The contribution of cytokines/chemokines in chronic pain has been well-established with a large amount of pre-clinical and clinical evidence [15; 19; 29; 30; 53; 73]. In recent years, there is a growing appreciation that autoimmunity could be one of the mechanisms for chronic pain [36]. In randomized controlled trials for rheumatoid arthritis, infusions of rituximab to deplete B cells significantly improved patients’pain experience [13].…”

Section: Discussionmentioning

confidence: 99%

Unbiased proteomic analysis detects painful systemic inflammatory profile in the serum of nerve injured mice

Zhou

Shi

Liu

et al. 2022

Preprint

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Neuropathic pain is a complex, debilitating disease that results from injury to the somatosensory nervous system. The presence of systemic chronic inflammation has been observed in chronic pain patients, but whether it plays a causative role remains unclear. This study aims to determine the perturbation of systemic homeostasis by an injury to peripheral nerve and its involvement in neuropathic pain. We assessed the proteomic profile in the serum of mice at one-day and one-month following partial sciatic nerve injury (PSNL) or sham surgery. We also assessed mouse mechanical and cold sensitivity in naive mice after receiving intravenous administration of serum from PSNL or sham mice. Mass spectrometry-based proteomic analysis revealed that PSNL resulted in a long-lasting alteration of serum proteome, where the majority of differentially expressed proteins were in inflammation related pathways, involving cytokines/chemokines, autoantibodies and complement factors. While transferring sham serum to naive mice did not change their pain sensitivity, PSNL serum significantly lowered mechanical thresholds and induced cold hypersensitivity in naive mice. With broad anti-inflammatory properties, bone marrow cell extracts (BMCE) not only partially restored serum proteomic homeostasis, but also significantly ameliorated PSNL-induced mechanical allodynia, and serum from BMCE-treated PSNL mice no longer induced hypersensitivity in naive mice. These findings clearly demonstrate that nerve injury has a long-lasting impact on systemic homeostasis, and nerve injury associated systemic inflammation contributes to the development of neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Unbiased proteomic analysis detects painful systemic inflammatory profile in the serum of nerve injured mice

Zhou

Shi

Liu

et al. 2022

Preprint

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“…express immune regulators and cytokine signalling and contribute to immunity [70,71]. Dys-regulation in the bidirectional signalling between the nociceptive and immune systems may be associated with excitation [72]. The nociceptors are in direct association or near association with nociceptive Schwann cells in the epidermis and form a mesh-like network [73,74].…”

mentioning

confidence: 99%

Thermal Pain Thresholds Are Significantly Associated with Plasma Proteins of the Immune System in Chronic Widespread Pain—An Exploratory Pilot Study Using Multivariate and Network Analyses

Gerdle

Wåhlén

Gordh

et al. 2021

JCM

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Chronic widespread pain (CWP), including fibromyalgia (FM), is characterized by generalized musculoskeletal pain. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for different stimuli such as heat (HPT) and cold (CPT). There is a growing interest in investigating the activated neurobiological mechanisms in CWP. This explorative proteomic study investigates the multivariate correlation pattern between plasma and muscle proteins and thermal pain thresholds in CWP and in healthy controls (CON). In addition, we analysed whether the important proteins and their networks for CPT and HPT differed between CWP and CON. We used a proteomic approach and analysed plasma and muscle proteins from women with CWP (n = 15) and CON (n = 23). The associations between the proteins and CPT/HPT were analysed using orthogonal partial least square (OPLS). The protein–protein association networks for the important proteins for the two thermal pain thresholds were analysed using STRING database. CWP had lowered pain thresholds for thermal stimulus. These levels were generally not related to the included clinical variables except in CWP for HPT. Highly interacting proteins mainly from plasma showed strong significant associations with CPT and HPT both in CWP and in CON. Marked differences in the important proteins for the two thermal pain thresholds were noted between CWP and CON; more complex patterns emerged in CWP. The important proteins were part of the immune system (acute phase proteins, complement factors, and immunoglobulin factors) or known to interact with the immune system. As expected, CWP had lowered pain thresholds for thermal stimulus. Although different proteins were important in the two groups, there were similarities. For example, proteins related to the host defence/immunity such as acute phase proteins, complement factors, immunoglobulin factors, and cytokines/chemokines (although not in CON for CPT) were important habitual/tonic factors for thermal pain thresholds. The fact that peripheral proteins contribute to thermal pain thresholds does not exclude that central factors also contribute and that complex interactions between peripheral and central factors determine the registered pain thresholds in CWP.

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“…Autoimmune mechanisms are also suggested to be involved in chronic pain ( 177 ). Autoantibodies were identified as molecules that can play a role in the neuroimmune interplay in pain in RA.…”

Section: The Neuroimmune Crosstalk In Joint Disordersmentioning

confidence: 99%

“…RF and ACPA ( 178 )] and are able to increase nociceptors hyperexcitability, inducing pain ( 179 ). The autoantibodies activate the complement system, increasing the inflammatory response and indirectly promoting nociception ( 177 ). On the other hand, autoantibodies also interact directly with the nociceptors through binding to the Fc gamma receptors and disrupting the ion channels ( 177 ).…”

Section: The Neuroimmune Crosstalk In Joint Disordersmentioning

confidence: 99%

“…The autoantibodies activate the complement system, increasing the inflammatory response and indirectly promoting nociception ( 177 ). On the other hand, autoantibodies also interact directly with the nociceptors through binding to the Fc gamma receptors and disrupting the ion channels ( 177 ). The injection of ACPA was shown to induce nociception in mice ( 180 ).…”

Section: The Neuroimmune Crosstalk In Joint Disordersmentioning

confidence: 99%

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The Neuroimmune Interplay in Joint Pain: The Role of Macrophages

et al. 2022

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Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.

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Autoimmune regulation of chronic pain

Abstract: Autoantibodies can contribute to peripheral and central sensitization through activation of complement pathway, activation of neuronal Fc gamma receptors, and disrupted function of neuronal ion channels.

Cited by 34 publications

References 186 publications

Unbiased proteomic analysis detects painful systemic inflammatory profile in the serum of nerve injured mice

Unbiased proteomic analysis detects painful systemic inflammatory profile in the serum of nerve injured mice

Thermal Pain Thresholds Are Significantly Associated with Plasma Proteins of the Immune System in Chronic Widespread Pain—An Exploratory Pilot Study Using Multivariate and Network Analyses

The Neuroimmune Interplay in Joint Pain: The Role of Macrophages

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