Cargando…
Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level
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 s...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963077/ https://www.ncbi.nlm.nih.gov/pubmed/37259426 http://dx.doi.org/10.3390/ph16020282 |
_version_ | 1784896161899872256 |
---|---|
author | Yu, Peng-Cheng Hao, Cui-Yun Fan, Ying-Zhe Liu, Di Qiao, Yi-Fan Yao, Jia-Bao Li, Chang-Zhu Yu, Ye |
author_facet | Yu, Peng-Cheng Hao, Cui-Yun Fan, Ying-Zhe Liu, Di Qiao, Yi-Fan Yao, Jia-Bao Li, Chang-Zhu Yu, Ye |
author_sort | Yu, Peng-Cheng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9963077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99630772023-02-26 Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level Yu, Peng-Cheng Hao, Cui-Yun Fan, Ying-Zhe Liu, Di Qiao, Yi-Fan Yao, Jia-Bao Li, Chang-Zhu Yu, Ye Pharmaceuticals (Basel) Article 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. MDPI 2023-02-13 /pmc/articles/PMC9963077/ /pubmed/37259426 http://dx.doi.org/10.3390/ph16020282 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yu, Peng-Cheng Hao, Cui-Yun Fan, Ying-Zhe Liu, Di Qiao, Yi-Fan Yao, Jia-Bao Li, Chang-Zhu Yu, Ye Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level |
title | Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level |
title_full | Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level |
title_fullStr | Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level |
title_full_unstemmed | Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level |
title_short | Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level |
title_sort | altered membrane expression and function of cd11b play a role in the immunosuppressive effects of morphine on macrophages at the nanomolar level |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963077/ https://www.ncbi.nlm.nih.gov/pubmed/37259426 http://dx.doi.org/10.3390/ph16020282 |
work_keys_str_mv | AT yupengcheng alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT haocuiyun alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT fanyingzhe alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT liudi alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT qiaoyifan alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT yaojiabao alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT lichangzhu alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel AT yuye alteredmembraneexpressionandfunctionofcd11bplayaroleintheimmunosuppressiveeffectsofmorphineonmacrophagesatthenanomolarlevel |