Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways

Prado, Judith; Westerink, Remco H.S.; Popov-Celeketic, J.; Steen-Louws, C.; Pandit, Aridaman; Versteeg, Sabine; Worp, Wouter R. P. H. van de; Kanters, Deon; Reedquist, Kris A.; Koenderman, Leo; Hack, C. E.; Eijkelkamp, Niels

doi:10.1073/pnas.2009647118

Cited by 27 publications

(22 citation statements)

References 79 publications

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“…However, both M2 and IL4-10 FP may also directly target sensory neurons. For example, IL-10 inhibits spontaneous activity of sensory neurons (Krukowski et al, 2016) and the IL4-10 fusion protein acts on microglia and sensory neurons (Eijkelkamp et al, 2016;Prado et al, 2021). Moreover, M2 macrophages resolve pain by transferring mitochondria to sensory neurons (Raoof et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain

et al. 2021

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Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Na v 1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain.

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Section: Discussionmentioning

confidence: 99%

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain

et al. 2021

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“…However, recently we have shown that IL4-10 FP when injected intrathecally inhibits inflammatory pain through direct signaling to sensory neurons. 15 Indeed various studies showed that cytokines, such as IL-10 and IL-4 may have direct effects on neurons and control their excitability. 25 - 29 Although IL4-10 FP may have direct analgesic properties through direct effects on sensory neurons, subchondral bone osteoclasts and chondrocytes also contribute to OA pain 30 , 31 and are known to express IL-4 and IL-10 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…11 IL4-10 FP inhibits pain in a mouse model for persistent inflammatory pain through inhibition of spinal neuroinflammation and inhibiting sensory neurons. 14,15 In addition, IL4-10 FP has chondroprotective and anti-inflammatory effects in in vitro and in vivo models for hemophilic arthropathy 16 as well as in human in vitro OA models. 17 In order to achieve a high concentration in the joint and ensure maximal penetration into the joint issues while minimizing systemic side effects, the IL4-10 FP is specifically developed for intra-articular application.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

et al. 2021

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Objective Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. Design rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. Results Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. Conclusion rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

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“…Neutrophils will be released into circulation upon encountering multiple danger signals by producing inflammatory cytokines. Moreover, monocytes will differentiate into tissue macrophages by phagocytosis of damaged cells and other invading pathogens [2], [3].…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory activity of Indonesian nutmeg seeds (Myristica fragrans Houtt): A topical gel formulation

Ikhsanudin

Lolita

Rais

2021

IJPHS

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Herbal medicines have been shown as anti-inflammatory with potentially lesser side effects. The active compound of nutmeg seed is proven to accelerate the healing process of inflammation. This study aimed to evaluate the gel formulation of Indonesian nutmeg (Myristica fragrans Houtt) seed extract for anti-inflammatory activity. A true experimental post test only with control group design was used in this study. The gel was formulated with various concentrations of nutmeg seed extract, namely formulations F1 (0%), F2 (2%), F3 (4%), F4 (8 %), and F5 (12%). Analysis of variance (ANOVA) followed by the least significant difference (LSD) methods were performed with SPSS version 22. The results showed that all formulas had an opaque physical appearance, brownish-yellow color, soft texture, and aromatic odor. The increase of extract concentration in gel formula will affect the adhesion and spreadability. F5 showed the highest anti-inflammatory activity compared to other groups. This formula was generally identified as having a good physical appearance, homogeneity, and stability with a pH value of 6.16±0.24, adhesiveness of 51.12±0.15 sec, and a spreadability of 19.54±0.12 cm2. Therefore, Indonesian nutmeg has the potential to be well-acceptable as a candidate for topical anti-inflammatory agents in global health benefits.

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Cytokine receptor clustering in sensory neurons with an engineered cytokine fusion protein triggers unique pain resolution pathways

Cited by 27 publications

References 79 publications

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain

IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

Anti-inflammatory activity of Indonesian nutmeg seeds (Myristica fragrans Houtt): A topical gel formulation

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