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A novel method to characterize AUD\u2010related immune signaling involves probing Toll\u2010like receptor (TLR)\u20104 stimulated monocyte production of intracellular cytokines (ICCs) via lipopolysaccharide (LPS). We evaluated relationships between AUD and ICC production at rest and after LPS stimulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed blood samples from 36 participants (AUD <jats:italic>N<\/jats:italic>\u2009=\u200914; Controls <jats:italic>N<\/jats:italic>\u2009=\u200922), collected across time, with ICC expression assessed at rest (i.e., unstimulated) and following stimulation with LPS (i.e., a total of 5 repeated unstimulated or stimulated measures\/participant). Markers assessed included tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), interleukin\u20106 (IL\u20106), TNF\u2010\u03b1 and IL\u20106 co\u2010expression, and interferon (IFN). For each marker, we constructed linear mixed models with AUD, LPS, and timepoint as fixed effects (BMI as covariate), allowing for random slope and intercept. AUD\u2009\u00d7\u2009LPS was included as an interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>For TLR4\u2010stimulated monocyte production of TNF\u2010\u03b1, there were effects of AUD (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), LPS (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), and AUD\u2009\u00d7\u2009LPS interaction (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), indicating that individuals with AUD showed greater unstimulated\u2010 and stimulated monocyte expression of TNF\u2010\u03b1. Similarly, for TLR4\u2010stimulated monocyte co\u2010expression of TNF\u2010\u03b1 and IL\u20106, there were effects of AUD (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), LPS (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), and AUD\u2009\u00d7\u2009LPS interaction (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). No AUD or LPS effects were found for IL\u20106. Timepoint effects were observed on IL\u20106 and TNF\u2010\u03b1\/IL\u20106 co\u2010expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Finally, for IFN there were also effects of AUD (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), LPS (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), and AUD\u2009\u00d7\u2009LPS (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Individuals with AUD showed greater resting or unstimulated levels of intracellular monocyte expression of TNF\u2010\u03b1 and IL\u20106\/TNF\u2010\u03b1 co\u2010expression than controls. AUD was associated with increases in TLR4\u2010stimulated monocyte production of TNF\u2010\u03b1 and co\u2010production of IL\u20106 and TNF\u2010\u03b1. This is, to our knowledge, the first study to investigate relationships between AUD and monocyte production of proinflammatory cytokines, at rest and in response to TLR4 stimulation with LPS. The study extends previous findings on the roles of proinflammatory cytokines in AUD and serves as a critical proof of concept for the use of this method to probe neuroimmune mechanisms underlying AUD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15173","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T07:04:33Z","timestamp":1692947073000},"page":"1859-1868","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Alcohol use disorder (<scp>AUD<\/scp>) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4005-5885","authenticated-orcid":false,"given":"Elizabeth M.","family":"Burnette","sequence":"first","affiliation":[{"name":"Department of Psychology University of California at Los Angeles  Los Angeles California USA"},{"name":"Neuroscience Interdepartmental Program 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