Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms

Abstract

Neuroimmune interactions may contribute to severe pain and regional inflammatory and autonomic signs in complex regional pain syndrome (CRPS), a posttraumatic pain disorder. Here, we investigated peripheral and central immune mechanisms in a translational passive transfer trauma mouse model of CRPS. Small plantar skin–muscle incision was performed in female C57BL/6 mice treated daily with purified serum immunoglobulin G (IgG) from patients with longstanding CRPS or healthy volunteers followed by assessment of paw edema, hyperalgesia, inflammation, and central glial activation. CRPS IgG significantly increased and prolonged swelling and induced stable hyperalgesia of the incised paw compared with IgG from healthy controls. After a short-lasting paw inflammatory response in all groups, CRPS IgG-injected mice displayed sustained, profound microglia and astrocyte activation in the dorsal horn of the spinal cord and pain-related brain regions, indicating central sensitization. Genetic deletion of interleukin-1 (IL-1) using IL-1αβ knockout (KO) mice and perioperative IL-1 receptor type 1 (IL-1R1) blockade with the drug anakinra, but not treatment with the glucocorticoid prednisolone, prevented these changes. Anakinra treatment also reversed the established sensitization phenotype when initiated 8 days after incision. Furthermore, with the generation of an IL-1β floxed(fl/fl)mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1β, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred disease phenotype. These results indicate that persistent CRPS is often contributed to by autoantibodies and highlight a potential therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.

Heterogeneous presentation of caspr2 antibody‐associated peripheral neuropathy – A case series

“…Further insight into the interaction of immunity and pain arises from very recent findings from chronic CRPS patients. IgG transfer from CRPS patients into previously injured mice led to pain‐like behaviour and sustained microglia and astrocyte activation in the dorsal horn of the spinal cord and pain‐related brain regions, indicating central pain sensitization (Helyes et al., 2019). The effect was mediated via the interleukin‐1ß (IL‐1β) and conditional knockout of IL‐1β or blockade with the antagonist anakinra reversed the effect.…”

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains

“…After TBS washes, sections were incubated for 2 h at RT with peroxidase conjugated donkey anti-chicken IgG (Jackson ImmunoResearch Laboratories Inc., West Grove, PA, USA), diluted 1:500 in blocking buffer. Visualization were performed using nickel(II) sulfate hexahydrate/3,3′-diaminobenzidine tetrahydrochloride (Merck KGaA) as chromogen and glucose oxidase (Merck KGaA) [ 49 ]. Sections were mounted onto gelatinized slides, allowed to dry overnight, transferred into ascending ethanol solutions (50%, 70%, 96%, absolute for 5 min, respectively), then cover slipped with PERTEX mounting medium.…”

Cell-specific conditional deletion of interleukin-1 (IL-1) ligands and its receptors: a new toolbox to study the role of IL-1 in health and disease

“…To overcome these limitations, the Cre/loxP system that allows selective/conditional deletion of targeted genes was recently used to generate new mouse mutant lines to allow cell-specific conditional deletion of IL-1 ligands and its receptors in a Cre recombinase-dependent manner (loxP-flanked, abbreviated as fl/fl). To this end, we have recently reported the generation and characterization of new IL-1α fl/fl and IL-1β fl/fl mouse lines [ 39 , 40 ] generated from Il1a tm1a(EUCOMM)Wtsi (clone EPD0822-4-H02) or Il1b tm1a(EUCOMM)Hmgu (clone HEPD0840-8-E03) embryonic stem cells purchased from the European Mouse Mutant Cell Repository (EuMMCR). The full description of the gene targeting strategies for both IL-1α fl/fl and IL-1β fl/fl mice as well as experimental procedure from initial culturing and microinjection of ES cells leading to the generation of mice allowing for the conditional deletion of IL-1α and IL-β are published [ 39 , 40 ].…”

“…To this end, we have recently reported the generation and characterization of new IL-1α fl/fl and IL-1β fl/fl mouse lines [ 39 , 40 ] generated from Il1a tm1a(EUCOMM)Wtsi (clone EPD0822-4-H02) or Il1b tm1a(EUCOMM)Hmgu (clone HEPD0840-8-E03) embryonic stem cells purchased from the European Mouse Mutant Cell Repository (EuMMCR). The full description of the gene targeting strategies for both IL-1α fl/fl and IL-1β fl/fl mice as well as experimental procedure from initial culturing and microinjection of ES cells leading to the generation of mice allowing for the conditional deletion of IL-1α and IL-β are published [ 39 , 40 ]. In these new alleles, exon 4 of the Il1a gene (for IL-1α fl/fl mice) or exon 4–5 of the Il1b gene (for IL-1β fl/fl mice) flanked with loxP sites can be deleted by Cre recombinase, leading to exon 4 or 4–5 deletion and generation of cell-specific IL-1α and IL-1β-deficient allele, respectively (Fig.…”

“…Table 1 provides a list of the cell-/tissue-specific deficient mice in IL-1α, IL-1β, IL-1R1, and IL-1R2 generated to date that have been tested under different inflammatory paradigms. While the generation of cell-specific IL-1α and IL-1β-deficient lines is limited, due to the recent generation of IL-1α fl/fl and IL-1β fl/fl mice, the first studies using those models have demonstrated the critical role of microglial IL-1β in the establishment of pain in the context of complex regional pain syndrome [ 39 ], while cardiomyocyte-derived IL-1α has been found not to contribute to tissue remodeling during myocardial infarction [ 40 ]. In contrast, IL-1R1 fl/fl mice have generated various cell-/tissue-specific IL-1R1-deficient lines, most studies showing a critical role for IL-1 signaling in immune cell activation and vascular activation in various models of peripheral infection and chronic inflammation (see Table 1 ).…”