Section 5 (Table 5):
Mechanisms that can interact with immune and inflammatory functions as part of the phenomenology of OUD
| Mechanism | Molecular Target(s) | Effect | Source (central vs. peripheral) | Citation |
|---|---|---|---|---|
| Sex | ||||
| Diverse immune-related genes and micro-RNA are X-linked in humans | Genes Include: CD40L, CD99, CRFL2, CXCR3, GMCSFR, IL2RG, IL3RA, IL13RA2, IL9R, IL13RA1, IRAK1, TLR7, TLR8 |
Sex as a complex mediating variable in different neuroimmune aspects of OUD. | Potentially both, depending on mechanism and contextual variables. | (Libert, et al., 2010) |
| Neurosteroid effects on innate immune function in macrophages | Likely TLR4 | Allopreganolone (positive modulator of GABA-receptor) has sex-specific immunomodulatory effects after LPS in vitro exposure | In vitro study | (Balan et al., 2022) |
| Sex affects cytokine responses to LPS. | Likely TLR4 and other mechanisms (IL6, IL-10, TNF-α) | Female cells respond to LPS with higher IL-10 and lower TNF-α than males. | In vitro study | (Rodas, et al., 2021) |
| Differential transcriptional effects of X-liked in genes in leukocytes | TLR4 and other mechanisms | Leukocytes from males and females show sex-specific changes in transcription of 54 genes, after LPS. | In vitro LPS stimulation | (Stein et al., 2021) |
| i.v. LPS and hyperalgesia | TLR4 and other mechanisms | fMRI responses to inflammatory pain in rACC differ between sexes | Central responses | (Karshikoff et al., 2016, Karshikoff et al., 2015) |
| Poly-drug Use | ||||
| Smoking status affects cytokine responses to LPS. | Likely TLR4 and other mechanisms (IL6, IL-10, TNF-α) | Smoking status Predicts differential cytokine responsiveness to LPS stimulation | In vitro study | (Rodas, et al., 2021) |
| Microglial imaging in persons with AUD | Effects of chronic alcohol on microglial function. | Brain TSPO binding lower in persons with AUD, but only if they were stratified by genotype | Brain PET study with TSPO radiotracer (11C-PBR-28) | (Kalk et al., 2017, Kim, et al., 2018) |
| Stress exposure | ||||
| Acute social stress in males n=44 (age 21–65). | Acute psychological stress effects on HPA axis and neuroimmune function |
Acute social stress causes ↓TNF-α and ↓IL-6 after LPS in vitro stimulation | Potentially central and hypothalamic, based on social stress exposure | (Wirtz, et al., 2007) |
| PTSD and cytokine levels (n=28, 50% females, mean age 41–42). | Chronic PTSD affects peripheral cytokines | ↑levels of several pro-inflammatory cytokines in PTSD vs. controls: esp. TNF-α, IFN-γ, IL-6 and IL-1β | Unclear | (Hoge, et al., 2009) |
| Sleep and Circadian Rhythm | ||||
| Simulated night shift work effects on cytokines (n=10, 90% male, mean age 27). | 4 days of simulated night shift | Disruption in circadian cycle of cytokines in response to stimulation | Propose several central and peripheral mechanisms | (Cuesta, et al., 2016) |
| Chronic insomnia and cytokine function (n=11 young adults, 55% male). | 4-day sleep study | Disruption of cytokine release in persons with insomnia (↑IL-6 and TNF-α, as well as cortisol in the daytime, compared to controls). | Diverse mechanisms possible (including HPA axis disruption) | (Vgontzas, et al., 2002) |
AUD: Alcohol use disorder
HPA: hypothalamo-pituitary adrenal axis
LPS: Lipopolysaccharide (experimental TLR4 agonist stimulus)
rACC: rostral anterior cingulate cortex
TSPO: 18KDa-translocator protein; marker for activated microglia