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Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling., (©2022 American Association for Cancer Research.)

Objective: To evaluate the role of neutrophil extracellular traps (NETs) in the genesis of joint hyperalgesia using an experimental model of arthritis and transpose the findings to clinical investigation., Methods: C57BL/6 mice were subjected to antigen-induced arthritis (AIA) and treated with Pulmozyme (PLZ) to degrade NETs or Cl-amidine to inhibit NET production. Oedema formation, the histopathological score and mechanical hyperalgesia were evaluated. NETs were injected intra-articularly in wild type (WT), Tlr4-/-, Tlr9-/-, Tnfr1-/- and Il1r-/- mice, and the levels of cytokines and Cox2 expression were quantified. NETs were also quantified from human neutrophils isolated from RA patients and individual controls., Results: AIA mice had increased NET concentration in joints, accompanied by increased Padi4 gene expression in the joint cells. Treatment of AIA mice with a peptidyl arginine deiminase 4 inhibitor or with PLZ inhibited the joint hyperalgesia. Moreover, the injection of NETs into joints of naïve animals generated a dose-dependent reduction of mechanical threshold, an increase of articular oedema, inflammatory cytokine production and cyclooxygenase-2 expression. In mice deficient for Tnfr1, Il1r, Tlr4 and Tlr9, joint hyperalgesia induced by NETs was prevented. Last, we found that neutrophils from RA patients were more likely to release NETs, and the increase in synovial fluid NET concentration correlated with an increase in joint pain., Conclusion: The findings indicate that NETs cause hyperalgesia possibly through Toll-like receptor (TLR)-4 and TLR-9. These data support the idea that NETs contribute to articular pain, and this pathway can be an alternative target for the treatment of pain in RA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a μM concentration range: CBD (IC 50  = 15 μM) and DMH-CBD (IC 50  = 38 μM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC 50  = 58 μM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A 2A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A 2A receptor dependent-manner., (Copyright © 2019 Elsevier Inc. All rights reserved.)