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Morphine disrupts antigen-presenting cell function through TLR-4 and autophagy pathways
BACKGROUND: Morphine dependence is a major challenge worldwide. Besides, it has many adverse effects and suppresses its user's immune systems. Antigen-presenting cells (APCs) play a crucial role in activating T cells, thereby protecting us from various diseases. Therefore, understanding the influence of morphine on APC function may reveal its impact on immune modulation. METHODS: Macrophages and dendritic cells (DCs) were cultured with morphine and assessed for antigen uptake, processing, and presentation using flow cytometry, confocal microscopy, and colony-forming units (CFU). TLR-4 involvement was examined through gene silencing and pharmacological inhibition. Autophagy markers (LC3, Atg7, Atg12) were analyzed by RT-qPCR and immunofluorescence. RESULTS: We observed that morphine inhibited antigen uptake, as evidenced by reduced phagocytosis of Mycobacterium tuberculosis (Mtb), E. coli, and other antigens. Further, it inhibited the killing of Mtb and E. coli and the processing of their antigens, as evidenced by reduced colocalization of LC3/LAMP1 with Mtb and E. coli. It prevented LC3 colocalization with the lysosomal marker LAMP1. Furthermore, morphine impaired antigen presentation, as evidenced by downregulation of MHC I, MHC II, CD80, and CD86, and reduced activation of CD4 T cells. Additionally, we observed that morphine exerted its mechanistic effects for immunosuppression through the TLR-4/NF-Ä¸B and autophagy pathways. CONCLUSION: This study identifies a mechanism by which morphine suppresses immune function by impairing antigen uptake, processing, and presentation in antigen-presenting cells through TLR-4-dependent autophagy pathways. These findings provide important insights into opioid-induced immunosuppression and have direct clinical relevance for the use of morphine in immunocompromised individuals.
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