Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level

Abstract

Morphine, one of the most efficacious analgesics, is effective in severe pain, especially in patients with concomitant painful cancers. The clinical use of morphine may be accompanied by increased immunosuppression, susceptibility to infection and postoperative tumor metastatic recurrence, and the specific mechanisms and clinical strategies to alleviate this suppression remain to be investigated. Expression of CD11b is closely associated with the macrophage phagocytosis of xenobiotic particles, bacteria or tumor cells. Here, we find that morphine at 0.1–10 nM levels inhibited CD11b expression and function on macrophages via a μ-opioid receptor (MOR)-dependent mechanism, thereby reducing macrophage phagocytosis of tumor cells, a process that can be reversed by thymopentin (TP5), a commonly used immune-enhancing adjuvant in clinical practice. By knocking down or overexpressing MOR on macrophages and using naloxone, an antagonist of the MOR receptor, and LA1, a molecule that promotes macrophage CD11b activation, we suggest that morphine may regulate macrophage phagocytosis by inhibiting the surface expression and function of macrophage CD11b through the membrane expression and activation of MOR. The CD47/SIRPα axis, which is engaged in macrophage-tumor immune escape, was not significantly affected by morphine. Notably, TP5, when combined with morphine, reversed the inhibition of macrophage phagocytosis by morphine through mechanisms that promote membrane expression of CD11b and modulate its downstream signaling (e.g., NOS2, IFNG, IL1B and TNFA, as well as AGR1, PDGFB, IL6, STAT3, and MYC). Thus, altered membrane expression and function of CD11b may mediate the inhibition of macrophage phagocytosis by therapeutic doses of morphine, and the reversal of this process by TP5 may provide an effective palliative option for clinical immunosuppression by morphine.

Morphine acts in vitro to directly prime nociceptors

“…DRG cultures were prepared from whole DRGs not cleared of non-neuronal cells. While it has been reported that these cells express MOR and can act indirectly to contribute to sensitization of DRG neurons 44 , 45 by an activated of immune response, in vivo 46 – 48 However, we prepared low-density DRG neuronal cultures that were used within 3 days, at which time there is minimal growth of non-neuronal cells and nociceptor neurites. This approach has allowed us to patch nociceptors without neighboring non-neuronal cells within > 100 µm.…”

Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity

“…The downregulation of the cannabinoid receptor gene expression in the tramadol-treated group suggests that this opioid alters the signaling of the active zone in the presynaptic terminals, consequently affecting synaptic plasticity and reducing neurotransmitter release probability. The expression of the gene encoding for CD11b, a microglia biomarker, is associated with leukocyte adhesion and inflammatory cell migration [ 103 ]. As a decrease in the expression of the CD11b-encoding gene was observed in both opioid-treated groups, an immunosuppressive effect might be deduced for tramadol and tapentadol, particularly affecting macrophage-induced phagocytosis.…”

Unveiling the Potential of BenzylethyleneAryl–Urea Scaffolds for the Design of New Onco Immunomodulating Agents

“…Finally, the compounds were tested for their effect on CD11b and CD80 expression in THP-1 cells co-cultured with HT-29. While the effect on CD80 expression was very mild (less than 10% of inhibition rates), all of the compounds tested were found to significantly reduce CD11b expression, which is a promising target for immunomodulation in anticancer therapies [ 23 , 24 ]. In most of the cases, this effect was even higher than the one observed for the reference compound BMS-8.…”