Vipula R. Bataduwaarachchi
SMN Hansanie1
Neesha Rockwood
Leon Gerard D'Cruz- 1Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
- 2Research and Innovation Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
- 3Department of Microbiology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
- 4Department of Infectious Diseases, Imperial College London, London, United Kingdom
- 5School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
Epidemiological studies have shown high tuberculosis (TB) prevalence among chronic opioid users. Opioid receptors are found on multiple immune cells and immunomodulatory properties of opioids could be a contributory factor for ensuing immunosuppression and development or reactivation of TB. Toll-like receptors (TLR) mediate an immune response against microbial pathogens, including Mycobacterium tuberculosis. Mycobacterial antigens and opioids co-stimulate TLRs 2/4/9 in immune cells, with resulting receptor cross-talk via multiple cytosolic secondary messengers, leading to significant immunomodulatory downstream effects. Blockade of specific immune pathways involved in the host defence against TB by morphine may play a critical role in causing tuberculosis among chronic morphine users despite multiple confounding factors such as socioeconomic deprivation, Human immunodeficiency virus co-infection and malnutrition. In this review, we map out immune pathways involved when immune cells are co-stimulated with mycobacterial antigens and morphine to explore a potential immunopathological basis for TB amongst long-term opioid users.
Introduction
Tuberculosis (TB) remains a longstanding global health challenge, claiming 1.5 million lives in 2020. Two-thirds of new cases come from the eight highest-burdened nations, with six of them in South and Southeast Asia. (1)population is latently infected with TB. The risk of reactivation of latent Mycobacterium tuberculosis (MTB) is rising due to international travel, migration, immunosuppressive co-morbidities, and medication use, affecting both developed and developing countries. (2) In order to achieve the World Health Organization goal of reducing 90% of new TB cases by 2035, it is vital to better understand the key causes of reactivation of latent TB. Multiple risk factors for TB are clustered in different subpopulations. (3–5) Epidemiological data have shown that long-term opioid users are more susceptible to TB than the rest. (6) As per a comprehensive community-based case-control study, higher TB risk was independently associated with tobacco smoking, drug use (especially injectable drugs OR = 5.67; 95%CI: 2.68, 11.98), homelessness and area-level deprivation. The strongest risk factor among the intermediate social determinants was misuse of class A injectable drugs (e.g., Ecstasy, Cocaine, Crack Cocaine, Heroin), with five times higher TB odds (OR = 5.67; 95%CI = 2·68, 11.98) compared to those who never misused class A drugs (adjusted for age, sex, BCG vaccination status and long stays in high TB area). (7) A multivariate analysis has shown that drug use was associated with smear-positive TB (OR 2.2, CI 311 – 401, p<0.001). (8) Even accounting for genetic, environmental, socio-economic, and culture-related risk factors, raises the possibility of an underlying immunopathological basis leading to immune suppression. (6, 9–11) TB is often the most common opportunistic infection in endemic areas. (11) This highlights the importance of exploring independent pathophysiological mechanisms causing immune impairment in chronic drug use separately in different infections despite the multiple confounding factors causing generalised immune suppression.
The World Drug Report of 2021 has reported that around 275 million people used illicit substances in 2020 globally, highlighting another growing health challenge. Opioids are the most heavily used substance. Over 75% of substance users live in developing countries, where the prevalence of TB is also highest. (12) Long-term use takes different forms, including misuse of prescription opioids, habitual use without dependence, and increased use as a long-term analgesic. (13) A recent review published in the Lancet has highlighted the TB burden among vulnerable groups worldwide with variable prevalence. (14) Table 1 further summarises studies assessing a link between drug use and TB. Except for one study, others point towards a strong link between drug use and TB risk. As multiple confounders co-exist in these vulnerable populations, causality cannot be independently assessed. Epidemiological data assessing TB infection among drug users taking it as an independent variable is a future need. More specific details of the nature of drug use and the immune status will further help fill the missing data gap.
Table 1 Summary of the epidemiological data assessing tuberculosis among drug users.
Immunomodulatory properties of opioids vary in the presence of different microbial antigens. Detailed characterisation of immune pathways affected by opioids in the presence of specific microbial pathogens is essential to characterise mechanisms of immunopathogenesis further. (20, 21) Due to the widespread testing of morphine in multiple previous pre-clinical studies (22), this review collates the immunomodulatory properties of morphine, and it suggests a potential role for opioids during chronic use in the immune pathogenesis of TB.
Opioid receptors in the immune system
Opioids act on their receptor (OR), a G protein-coupled receptor (GPCR). They are categorised into two distinct groups: classical OR, which includes morphine (mu) MOR, ketocyclazocine (kappa) KOR, and vas deferens (delta) DOR, and non-classical OR, which includes nociceptin Orphanin FQ peptide receptor (NOR). (23, 24) ORs are located in multiple immune cells, including macrophages and lymphocytes, and are widely distributed in the human body. Both endogenous opioid peptides and exogenous synthetic opioids with different molecular properties act on the same receptors, giving rise to variable downstream effects. (21, 25)
Chronic morphine administration is known to cause impairment of both innate and adaptive arms of the immune response. (26) The concept of direct and indirect morphine action was on the immune system first introduced through work in preclinical studies, which indicated that the MOR mediates morphine-induced immunosuppression and that although some functions are amplified in the presence of cortisol or sympathetic activation. (27) The activation of KOR has also been shown to reduce antibody production, inhibit phagocytic cell activity, inhibit T cell development and alter the production of various pro-inflammatory cytokines, chemokines, and the receptors for these mediators. (28) In vitro experiments have shown that the DOR agonist KNT-127 causes immune suppression in rat models with colitis. (29) It has further shown the functional differentiation of OR subtypes located on the immune cells responding differently to endogenous and exogenous opioids. The novel M3OR subtype has been characterised as an opioid peptide-insensitive and opiate alkaloid-selective GPCR that is functionally linked to constitutive nitric oxide synthase activation. Opioid peptides stimulate granulocyte and immunocyte activation and chemotaxis via the activation of a novel leukocyte D2OR subtype. However, opiate alkaloid M3OR agonists inhibit these same cellular activities. (30)
Chemokine receptors (CCR), which mediate chemokine response, belong to the same class of GPCR as OR and possibly share a common evolutionary origin. The evidence suggests that these receptors cross-desensitise each other, whereas morphine that binds to OR can block CCR signalling and vice versa. (31, 32) The mechanisms underlying heterogenous desensitisation could be the formation of receptor heterodimers and protein kinase C-mediated phosphorylation of Serine, Threonine and Tyrosine moieties. Heterogenous desensitisation may be one mechanism of immune suppression by opioids with high doses and long-term exposure. (33, 34) Bivalent molecules can be tested to modify the complex and its cellular effects. Different immune effects mediated by OR in the presence of mycobacterial antigens and morphine are discussed in the subsequent sections. Bivalent molecules that selectively modulate the OR-CCR complex have therapeutic potential, such as VZMC013, which targets the MOR-CCR5 heterodimer to inhibit opioid-exacerbated HIV1 entry into the immune cells. Similar molecules may have applications in managing opioid-induced immune suppression, including the potential TB risk (35).
Modulation of the immune cells and mediators by morphine
A focused literature search in Google Scholar, PubMed and Medline was carried out to extract the studies conducted to find the effects of ‘morphine’ on the ‘immune system’. Tables 2, 3 comprehensively summarise the immune cells and mediators influenced by morphine administration. Morphine suppresses multiple immune cells, including macrophages, which play a crucial role in the immunopathogenesis of TB. The consequences of morphine exposure extend to inhibiting chemotaxis and multiple cellular functions in macrophages, including respiratory burst activity, phagocytosis, and colony formation (Table 2).
Table 2 Effects of morphine on the immune cells.
Table 3 Morphine effects on the chemical mediators.
Suppression of the critical immune mediators such as tumour necrosis factor (TNF α), interferon (IFN γ), and nitrous oxide (NO) produced by macrophages was also reported in multiple studies (Table 3). Figure 1 illustrates the immune pathways affected during the co-stimulation of macrophages by mycobacterial antigens and morphine. Suppression of the neutral killer (NK) cell by morphine is modulated via direct and centralised mechanisms. Lymphocytes are inhibited by multiple means, including reduced cytotoxicity and altered CD4/CD8 cell ratios.
Figure 1 Illustration of the co-binding of M. tuberculosis (MTB) antigens and opioids with TLR4. Illustration of the co-binding of MTB antigens and opioids with TLR4. Co-stimulation of the TLR4 leads to MyD88-dependent and independent activation, leading to NFkB-dependent and independent mechanisms affecting chemical mediators downstream. [TLR, toll-like receptor; NF-κB, Nuclear factor-κB; TIRAP, Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein; TRIF, TIR-domain-containing adaptor-inducing interferon-β; TRAM, TRIF-related adaptor molecule].
The role of TLR during the interaction with mycobacterial antigens and morphine
TLRs are found in various immune cells and play a critical role in recognising molecular patterns of pathogens to trigger the immune system. Multiple TLRs, including TLR2, TLR4, TLR8, and TLR9, interact with various mycobacterial antigens. Morphine interacts with TLR2, TLR4, and TLR9, and co-stimulation by morphine and mycobacterial antigens may lead to complex immune effects downstream (49, 101–105).
Multiple mycobacterial antigens interact with immune cells via TLR-dependent and independent mechanisms. Figure 1 illustrates the co-binding of mycobacterial antigen and opioids with the TLR4 and its adaptor proteins. Rapidly growing, non-pathogenic mycobacteria containing AraLAM in their cell walls activate CD14 cells expressing TLR2 and macrophages. In contrast, slow-growing pathogenic MTB containing ManLAM has shown a relative inability to activate macrophages independent manner, potentially contributing to their virulence (Figure 2). However, other soluble and cell wall-associated mycobacterial antigens distinct from LAM can mediate immune cell activation via TLR. For example, a soluble heat-stable and protease-resistant factor mediates TLR2-dependent activation of immune cells, whereas a heat-sensitive cell-associated mycobacterial factor mediates TLR4-dependent activation of them. (106–112) Interestingly, induction of adaptive T cell response in TB does not require TLR2/4/9. In TLR2/4/9-deficient mice, mycobacterial replication is controlled by TLR-independent mechanisms to induce an adaptive T-cell response (113).
Figure 2 Illustration of the interactions by tuberculous antigens and morphine with the cell surface and intracellular receptors of a macrophage. The interaction between tuberculous antigens and morphine within macrophages. Morphine (M) and Mycobacterial antigens engage with TLR 2/4/9, while Mycobacterial antigens interact with NLR, MR, and Dectin-1. M enhances Mycobacterial antigen virulence by inhibiting TLR 2/4 and OR. Morphine influences various macrophage functions: (1) Desensitizing multiple CCRs via MOR and DOR. (2) Inhibiting FcR-mediated apoptosis via MOR, DOR, and KOR. (3) Enhancing TGF-induced apoptosis. (4) Impairing NO and SO synthesis, respiratory burst activity, and bacilli killing. NLR2 augments TLR 2/4 actions through cross-talk. (6) M inhibits NFκB-mediated cytokine and chemokine synthesis via OR-TLR cross-talk. TLR9 elicits a proinflammatory response with Mycobacterial antigens and M, while TLR2/4 induces an anti-inflammatory response. (7) MR, present in AM, regulates protective macrophage responses. MTB or ManLAM upregulates PPARγ via MR, increasing IL8, COX2, and PGE2. ManLAM generates an anti-inflammatory response, inhibiting proinflammatory TNF and IL12 while inducing immunosuppressive IL10 and TGF β. ManLAM signalling via TLR2 and TLR4 triggers chemokine secretion in monocytes, with M exerting inhibitory effects via TLR 2/4 (10). Dectin-1, in combination with TLR2, induces TNF production in macrophages, particularly in attenuated MTB strains (11). LM blocks TLR2-induced TNF biosynthesis, permitting MTB to evade the host immune response. Antigen-specific variations are noted, with M-induced immune suppression amplifying antigen virulence mechanisms. (A more detailed version of this figure legend is provided in the Online Data Supplement).
Morphine interacts with TLR2, TLR4, and CD14 cells, causing inhibitory effects. (Figures 2, 3) These effects of morphine are exerted on different immune cell types interrupting their functions, which are vital for the immune defence against TB. Further, endomorphin-1, the endogenous form of opioids, has been shown to down-regulate TLR expression as a part of the negative feedback control. Consequently, external opioids, when strongly influencing the same pathway, may contribute to impaired and delayed antigen processing. (114) Consequently, the cells’ capacity to interact with mycobacterial antigens and trigger a protective immune response is ultimately reduced.
Figure 3 Co-stimulation of OR, TLR, and NLR with mycobacterial antigens and morphine and their intracellular cross-talking. Interactions between Mycobacterial antigens, morphine (M), and various receptors within macrophages. Both M and Mycobacterial antigens engage TLR 2/4/9. Specific antigens (LTA, HSP, PE6) interact with TLR4, inducing proinflammatory cytokines and apoptosis. Several interactions and pathways are highlighted: (1) M and bacterial antigens induce cross-talk between TLR2 and NLR2, inhibiting IL23 synthesis. (2) PE6 triggers proinflammatory cytokines via TLR4, possibly blocked by M. (3) M indirectly induces HMGB1, promoting TLR4 upregulation. (4) TLR4/OR pathways activate MAPK with proinflammatory effects in the CNS. (5) Intracellular TLR4/OR cross-talk affects cytokine secretion. (6) M inhibits LPS-induced NFκB activity. (7) M and M. tuberculosis induce TLR9 expression with pro-inflammatory consequences. (8) TLR9 regulates mycobacteria-induced Th1 responses. (9) NLR2 activates NFκB and cross-talks with TLR9. (10) M influences apoptosis-related molecules. (11) TLR2 plays a role in cytokine production regulation. (12) β-arrestin-2 negatively regulates TLR2-mediated apoptosis. (13) TLR2 activates PI3K/Akt signalling with M. (14) AraLAM induces cell activation and MTB killing. (15) TLR2-dependent inhibition of TLR9-dependent IFN α/β expression leads to decreased MHC-I cross-processing. (16) β-arrestin-2 regulates GPCR desensitization. These interactions reveal intricate immune responses in tuberculosis and opioid co-stimulation. (A more detailed version of this figure legend is provided in the Online Data Supplement).
Cross-talk between receptors
Figure 3 summarises the cross-talk between OR, TLR, and nucleotide-binding and oligomerisation domain-like receptors (NLR) 2 via multiple cytosolic second messengers during the interaction with morphine and mycobacterial antigens. In the central nervous system, cross-taking between OR and TLR share common cytosolic molecules such as MAPK, β-arrestin-2/TRAF6 complex, and the DNA-binding protein HMGB1. (115) NLR2 on the immune cells interacts directly with mycobacterial antigens and cross-talks with TLR 2/9 to modulate the immune response. (61) Cross-talk between MOR and TLR in cancer models has shown decreased NK cytotoxicity, decreased leucocyte migration, suppression of mast cell recruitment, and the induction of M2 cell polarisation, which may contribute to the immune impairment in TB (116). Further exploration of the role of these compounds within the immune system in modulating cellular function is required.
Variations in the antigenic stimulation
Co-stimulation of TLRs with antigenic material of a pathogen, together with morphine, has shown entirely different effects than the binding of either alone. Extensive in vitro and in vivo studies have consistently shown that morphine binding to TLR4 triggers a proinflammatory cytokine response downstream. In contrast, its binding to OR (opioid receptors) elicits an anti-inflammatory response. (104, 117) We hypothesise that opioid compounds interact with TLR as other natural compounds, modulating the host immune response, and it needs direct testing of this in pre-clinical models in the presence of tuberculosis antigens. (Figure 3).
Morphine causes an antiinflammatory response in dendritic cells (DC) cells via TLR2 and NLR2 when co-stimulated with S. pneumoniae, in contrast to the proinflammatory response induced by S. pneumoniae alone (Figure 3). (49) Morphine has also been shown to inhibit the TLR9 pathway when co-binding with HIV, promoting its replication in macrophages. (105) Similar variations of the immune effects have been observed with morphine and mycobacterial antigens in preclinical studies. Plasmacytoid DC expresses TLR9 in both humans and mice. (118–120) M. tuberculosis and morphine cotreatment have significantly upregulated TLR9 expression in mice. Its role is more proinflammatory, enhancing the levels of critical cytokines including TNF α, (interleukin) IL1β, and IL6, which contrasts with the antiinflammatory response exerted by TLR2/4 when co-stimulated by the same. (20, 121) This contracting proinflammatory action of TLR9 compared to other TLRs indicates the downstream receptor action heterogeneity, possibly explained by the unique binding of TB antigens with TLR9.
Discussion
Immunomodulatory effects of morphine in the immunopathogenesis of tuberculosis
In the immunopathogenesis of tuberculosis, morphine exerts immunomodulatory effects, as depicted in Figure 4. The acquisition of TB bacilli occurs through the inhalation of respiratory droplets containing the organism. Morphine’s influence leads to the suppression of NK cells and DC, as highlighted in Table 1. Consequently, this suppression can impair the initial defence against TB bacilli, including nonspecific killing and antigen presentation by these cells, ultimately increasing the host’s susceptibility to TB infection.
Figure 4 Effects due to the interactions of mycobacterial antigens and morphine with the immune cells and their mediators in the context of TB immunopathogenesis. The impact of mycobacterial antigens and morphine (M) on immune responses in tuberculosis (TB) immunopathogenesis. (1) TB bacilli virulence factors trigger a robust immune response. (2) ESX-1 induces MMP9 and MMP1 secretion; M reduces MMP9 and elevates MMP1 levels. (3) Neutrophils reduce initial Mycobacterial load. (4) M enhances TGFβ, lowering reactive oxygen intermediates. (5) M modulates CCR and CCL levels, affecting IFNγ-positive CD4 T cell migration. (6) M inhibits IL23 by dendritic cells. (7) M inhibits IL8 from neutrophils. (8) M suppresses NK cells. (9) M suppresses B cell activity. (10) M inhibits IL1, TNFα, and IL12, impacting IFNγ-induced T cell responses. (11) M inhibits IFNγ and TNFα from Th1 cells. (12) M inhibits IL2 from T cells. (13) M induces Th2 cell differentiation. (14) M promotes M2 macrophage switch via IL4. (15) MMP9 inhibition leads to M2 macrophage transformation. (16) Methadone increases CTLA-4 expression with variable PD-1 expression, impacting immune regulation in TB. (A more detailed version of this figure legend is provided in the Online Data Supplement).
Effects on the TB granuloma
A TB granuloma is a unique pathological entity comprising activated macrophages, monocytes, DC, neutrophils, and T lymphocytes (Figure 4). An established granuloma contains infected activated macrophages and epithelioid cells forming a central necrotic core and activated macrophages and layers of CD4+ and CD8+ T cells defining a dense cellular wall encircling the necrotic core. (122, 123) It is a dynamic structure that controls two processes: the induction of apoptosis of infected macrophages and the recruitment of uninfected macrophages by creating a chemotactic gradient (123).
Granuloma formation is triggered by the mycobacterial virulence factor ESX-1 (124) It triggers matrix metallopeptidase (MMP)9 secretion by the epithelial cell matrix surrounding a granuloma (Figure 4). (125) It potentially induces the chemotaxis of macrophages via (chemokine ligand (CCL)7, a substrate for MMP9 produced by macrophages. (126–129) Both well-coordinated processes of new macrophage recruitment and infected macrophage apoptosis are essential to maintain the immune integrity of TB granulomas. Morphine decreases the levels of MMP9 and increases the tissue inhibitor of MMP1, dysregulating this process (Figure 4) (108).
Macrophages
Macrophages, crucial in granuloma formation, face inhibition through various mechanisms induced by morphine (Figure 2). When infected with M. tuberculosis, macrophages experience heightened caspase-8-dependent apoptosis due to TLR2 signalling. However, mycobacteria take advantage of this situation during the initial stages of infection, as they depend on macrophages to penetrate deeper tissues and subsequently undergo apoptosis to expand within the granuloma. (123, 130) Morphine causes enhancement of TLR9-induced apoptosis of macrophages by stimulating TLR9 signalling, and multiple chemical mediators also potentiate apoptosis (Figures 1, 2). (20, 59) The impact of the induction of apoptosis by morphine depends on the exact stage of the infection.
MOR located on macrophages inhibits chemotaxis, which supports the notion of an antiinflammatory role of MOR. (131) Morphine’s effects on phagocytosis were variable, with inhibition observed through a naloxone-reversible mechanism. Mycobacteria employ the cell wall-associated lipid Phthiocerol dimycocerosate (PDIM) to conceal underlying pathogen-associated molecular patterns (PAMPs), effectively evading the recruitment of microbicidal macrophages via TLR-dependent pathways. Additionally, a structurally related molecule called Surface-associated Phenolic glycolipid induces the expression of CCL2, leading to the recruitment and infection of CCR2-expressing macrophages. Morphine suppresses CCL2, counteracting this pathway and suppresses multiple chemokines important in chemotaxis (Table 3).
Lymphocytes
Studies have shown that the reduction in total T cell counts and altered CD4/CD8 cell ratios are caused by morphine. Suppression of IL2 levels by morphine leads to a drop in T cell count (Table 2). CTLA-4 and PD-1 are two members of the CD28 family of receptors involved in T-cell inhibition by morphine. (132–134) In murine studies, MOR agonists have been shown to upregulate the expression of MOR, DOR, CD28, CTLA-4, and PD-1, which suppresses T-cell response. However, chronic opioid use has led to increased expression of CTLA-4, with unchanged PD-1 expression favouring an anti-inflammatory response among humans. (135) Morphine further triggers the Th2 switch, which may impair the cytotoxic potential of T cells against TB bacilli (Figure 4). Further studies are required to explore variable immune effects caused by different opioids on T cells.
Neutrophils
Neutrophils are abundant in both early granulomas and late cavitary granulomas. (32, 136) They exhibit reduced NADPH oxidase-dependent mycobacterial killing when they ingest mycobacteria. However, their role in mediating the clearance of infected, dying macrophages appears to be host-protective. This mechanism lowers the mycobacterial load and reduces intercellular spread into uninfected macrophages. (123) The inhibition of neutrophils and IL8 secretion by morphine may lead to reduced neutrophil-mediated killing, increasing the risk of TB bacilli dissemination (Table 3).
Interferons
IL17 recruits Th1 cells that secrete antigen-specific IFN γ, inhibiting MTB growth. Th1-mediated IFN γ is the critical chemical controller in granuloma formation. M. tuberculosis induces an IFN γ response through TLR9’s action. (21) Once stimulated by TB antigens via TLRs, macrophages and DCs secrete cytokines, including IL-12 and IL23, to induce IFN-γ production by T and NK cells. IFN-γ increases phagocytosis, phagolysosomal fusion, oxidative burst, and other nonoxidative mechanisms. (137) For an effective T helper 1 (Th1, IFN-γ producer cells) differentiation, costimulation (e.g., CD40L-CD40 and CD28-CD80/CD86 interactions) and NF-κB dependent signalling are essential. (138) IFN γ deficiency leads to a failure in granuloma formation, with subsequent infiltration of neutrophils leading to cellular necrosis. (122, 123) Bloom et al. have shown that macrophage-induced NO is the primary bactericidal mechanism of macrophages. It is established that IFN γ is an inducer of macrophage inducible NO synthase that leads to the production of NO (Figure 2). (139) IL1β is another mediator induced by mycobacterial antigens, which upregulate iNOS and subsequent NO production. NO-mediated killing by macrophages is the primary mechanism for controlling mycobacterial replication. A hypothesis can be proposed that the inhibitory effects of morphine on IFN γ, NO, and IL1β may lead to a dysregulation of this process, ultimately exerting negative impacts on granuloma formation (Figure 4; Table 2). Therefore, the suppression of INF-γ by morphine induces multiple significant negative implications on the immune defence against TB.
The role of IFN α/β on TB immunity is highly variable in contrast to the protective role of IFN-γ. Type I IFNs (IFN α/β) are potent inhibitors of IL-12 production by macrophages, which induces IFN-γ. (140) Conversely, they induce IFN-γ production by T and NK cells in an IL-12-independent way. (141) IFNα/β is shown to reduce monocyte viability. compromises their bacteriostatic activity and antigen presentation ability. (142) Type I IFNs have been used as an adjunctive therapeutic agent for PTB patients harbouring multi-drug resistant MTB strains. (143, 144)Multiple studies have reported that the induction of Type I IFNs precedes the onset of clinical tuberculosis. (145, 146) MTB inhibits the production of IFN α/β in response to TLR9 signalling. Morphine further suppresses this, producing complex effects requiring further characterisation in controlled studies (Table 2; Figure 3).
Tumour necrosis factors
M. tuberculosis–induced TNF α production appears to be controlled via TLR2. (122) Both TNF α deficiency and excess can lead to granuloma necrosis. (147, 148) The TNF α signalling deficiency in mice produced disorganised tuberculous granulomas. (149, 150) Deficient TNF α signalling increases intra-macrophage mycobacterial load and accelerates the formation of disorganised granulomas, ultimately leading to granuloma necrosis (130, 151). Morphine has been shown to suppress TNFα levels in many studies, which may enhance the progression locally (Tables 2, 3). It may further affect disorganised secondary granuloma formation in distal organs, leading to disseminated disease.
Interleukins and chemokines
Morphine upregulates CCR expression while downregulating CCL levels, causing a net deficiency of CCL. (Figure 2) (21) IL6 stimulates macrophage and cytotoxic T-cell differentiation. At the same time, IL10 inhibits proinflammatory cytokines, blocks the generation of ROI and NOI, blocks antigen processing and presentation in different APCs, and diminishes T-cell responses. IL12 is a crucial cytokine in developing and maintaining type 1 cellular response in MTB infection. IL12 binds to its receptor IL12R-β2 and activates the JAK-STAT pathway, inducing IFN γ to differentiate CD4+ T cells into Th1 effectors. Preclinical evidence has shown that IL-12 p40−/− deficient mice could not control bacterial growth, which appeared to be linked to the absence of both innate and acquired sources of IFN-γ. (152) This shows the central role played by IL12 in the defence against TB infection. IL23 induces IL17 production by memory T cells, creating an inflammatory response by Th17 cells, and it generates protective cellular responses. Morphine blocks the synthesis of all these vital mediators and damages the chemical coordination in the immune defence against TB. Moreover, IL12 induces inflammation by suppressing TGF ß and stimulating NK cells, contributing to increased CCL2 and CCL3 levels. (153) However, this effect may be counteracted by overall anti-inflammatory actions caused by morphine and the virulence mechanisms of mycobacterial antigens. (Table 3, Figure 4).
Conclusion
Chronic morphine administration causes suppression of multiple protective immune pathways vital in the defence against MTB. Multiple cellular receptors in immune cells, including OR, TLR2, and NLR 2, play critical roles in immunosuppression via complex intracellular cross-talk. Various cell types and their mediators involved in granuloma formation are inhibited by morphine via multiple mechanisms. This leads to a state of immunodeficiency that likely contributes to the reactivation, progression, and dissemination of MTB. Further studies are required to characterise potential therapeutic immunomodulatory targets in chronic opioid users at risk of infection with/reactivation of MTB.
Limitations
In vitro and in vivo preclinical studies assessing the immunomodulatory properties of opioids have been mostly limited to the testing of morphine. Considering the wide structural diversity and functional variation of opioids, direct testing of other categories of opioids and their antagonists is needed to delineate further the postulated mechanisms of the immunopathogenesis of TB potentiated by chronic opioid use. The duration and dosage of morphine use in patients may vary widely, with the added effect of the landscape of genetic heterogeneity across cultures, the impact of this review may be biased towards findings reported from the majority of studies originating from the Western, further studies are desperately needed from third-world nations investigating this phenomenon associating opioid use and the predisposition to TB. Chronic opioid use is associated with confounding factors, socioeconomic deprivation, malnutrition and infections associated with IVDU which may contribute to immune suppression.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Author contributions
VB: Conceptualization, Data curation, Methodology, Software, Visualization, Writing – original draft. HS: Data curation, Formal Analysis, Writing – review & editing. NR: Supervision, Writing – review & editing. LD: Supervision, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Acknowledgments
I acknowledge the guidance and encouragement from Professor Anoop Chauhan and my colleagues from the Research Department, Portsmouth University Hospital, UK. Professor Francis Drobniewski (Professor of Global Health and Tuberculosis Infectious Diseases and Immunity) and Dr Brian Robertson from the Imperial College London, UK, provided valuable feedback.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265511/full#supplementary-material
Abbreviations
APC, Antigen presenting cell; AraLAM, Abinofuranosyl-capped lipoarabinomannan; BCG, Bacillus Calmette–Guérin; CTLA-4, Cytotoxic T lymphocyte-associated antigen-4; DNA, Deoxyribonucleic acid; ESX-1, ESAT-6 secretion system 1; HIV, Human immunodeficiency virus; HMGB1, High mobility group box 1; JAK-STAT, Janus kinase/signal transducers and activators of transcription; ManLAM, Mannosylated lipoarabinomannan; MAPK, Mitogen-activated protein kinase; NADPH, Nicotinamide adenine dinucleotide phosphate; NOI, Negative oxygen Ion; PAMP, Pathogen associated molecular patterns; PD-1, Programmed cell death protein 1; PDIM, Phthiocerol dimycocerosate; ROI, Reactive oxygen intermediates; TGF, Transferrin growth factor; TRAF6, Tumour Necrosis Factor Receptor Associated Factor 6; WHO, World Health Organization.
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Keywords: immunopathogenesis of tuberculosis, morphine, opioids, opioid receptors, toll-like receptors, immunosuppression
Citation: Bataduwaarachchi VR, Hansanie SMN, Rockwood N and D'Cruz LG (2023) Immunomodulatory properties of morphine and the hypothesised role of long-term opioid use in the immunopathogenesis of tuberculosis. Front. Immunol. 14:1265511. doi: 10.3389/fimmu.2023.1265511
Received: 23 July 2023; Accepted: 25 September 2023;
Published: 23 October 2023.
Edited by:
Aleksander M. Grabiec, Jagiellonian University, PolandReviewed by:
Anu Goenka, University of Bristol, United KingdomUma S. Gautam, Duke University, United States
Copyright © 2023 Bataduwaarachchi, Hansanie, Rockwood and D'Cruz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Vipula R. Bataduwaarachchi, vipula@pharm.cmb.ac.lk