Table 1.
Effect of TLR4/opioid receptor pathway crosstalk in peripheral immune cells.
| Opioid receptor | Cell type | Vivo/vitro | Pathway | Immunomodulatory effects | Inhibitor |
|---|---|---|---|---|---|
| MOR | Macrophages | BMDM, RAW 264.7, J774.1 cells; C57, TLR4/MOR knockout mice | Increase or decrease TLR4 mRNA and protein expression (89, 90). Potentiate autophagy initiation through TLR4/p38 pathway, but inhibit autophagosomal maturation though MOR pathway (91). Suppress LPS-activated NO and TNF-α production (92) | Compromise the capacity of macrophages to respond to LPS (89). Reduce the cell viability (92) and bacterial clearance (91). Increased bacterial load (91) and bacterial sepsis (93). Prevent macrophage recruitment to the wound site and decrease the wound closure and wound integrity (93) | Naltrexone (89), PTX (89) |
| Monocytes | THP-1 and other cells | Suppress LPS-induced IFN-α and PGE2 production (94). Inhibit LPS-stimulated IL-10, IL-12 (95), and arachidonic acid, PGE2, ROI, and NO2 production (96). Potentiate LPS-stimulated NF-κB DNA binding (95) | Decrease antiviral defense and inhibit their response to activating stimuli (94). Inhibit LPS-stimulated monocyte activation (95) and instauration of a hyporesponsive phenotype on DC development (96) | ||
| Mast cells | BMMCs cells, C57; MS deficient/reconstituted mice | Inhibit LPS-induced TNF-α (34, 38, 97) but not CCL2 release (38) | Resident mast cells mediate selective morphine immunosuppression (38) | ||
| Neutrophils | vitro | Inhibit LPS-induced p38, ERK1/2 pathway activation (37) and decrease TNF-α, IL-6 (37), and IL-8 production (37, 98). Inhibit LPS-induced NF-κB binding in a NO-dependent mechanism (99) | Reduce neutrophils recruitment to the wound site and decrease the wound closure and wound integrity and increase bacterial sepsis (93) | KOR antagonist (37), naloxone (98) | |
| NK cells | vitro | Increase IL-6 (naloxone) and granzymes A and B (TAK-242) production (100) | Decrease NK cell ability to induce apoptosis in K562 cells and suppress NK cell cytotoxic activity (100) | Naloxone (100), TAK-242 (100) | |
| DOR | Macrophages | RAW 264.7 cells; sepsis rat model | Increase LPS-induced TNF-α and NO production (101). Suppress LPS-induced release of HMGB (102). DOR2: inhibit p38 MAPK activation and expression of TNF-α and MIP-2 (103) | Potentiate LPS-stimulated macrophage functions (101). Suppress LPS-induced cell death and protect rats from sepsis (102) | |
| KOR | Macrophages | J774 and other cells | Inhibit LPS-stimulated nitrite (104, 105), TNF-α (104, 105), IL-10 (104) and iNOS (104), IL-1 (105) and IL-6 production (105). Decrease NO release (106) | Moderate anti-inflammatory effects (104). Inhibit the cytotoxicity of macrophages (106) | Naloxone (104), naloxone (partially) (105), norBNI (104, 105) |
| Monocytes | P388D1 and THP1 cells | Suppress LPS-stimulated IL-6 production (107). Inhibit LPS-induced NF-κB/p65 nuclear translocation and IL-1β, TNF-α release (108) | Anti-inflammatory effect (108) | nor-BNI (107), ML-190 (108) | |
| Neutrophils | Ischemia–reperfusion injured rat heart model | Attenuate the expressions of TLR4, NF-κB and TNF-α (109) | Inhibit neutrophil accumulation (109). Cardioprotective and anti-inflammatory effects (109) | nor-BNI (109) |
MOR, μ opioid receptor; DOR, δ opioid receptor; KOR, κ opioid receptor; BMDM, bone marrow-derived macrophages; RAW264.7 cells, mouse leukemic monocyte macrophage cell line; BMMC, bone marrow–derived mast cells; K562 cells, a chronic myelogenous leukemia-derived; P388D1 cells, a mouse monocyte-like cell line; THP-1, human monocytic cell line; NK, natural killer cells, MOR agonists, morphine, fentanyl, remifentanil, DAMGO, and endomorphin 1/2; DOR agonists, DADLE, SNC 80, and Deltorphin-dvariant; KOR agonists, Salvinorin A, U50488H, and dynorphin 1–17; norBNI, nor-binaltorphimine (a KOR-selective antagonist); ML-190, a selective KOP receptor antagonist; TAK-242 (TLR4 signaling antagonist).