Editorial: Immune Response Changes in Alcohol and non-Alcohol Associated Tissue Injury

PAUL THOMES ^*

• Auburn University, Auburn, United States

The research topic, "Immune Response Changes in Alcohol and Non-Alcohol Associated Tissue Injury," hosted by Frontiers in Immunology, brought together 10 articles. Six articles were related to alcohol-associated tissue injury, including two human studies and three rodent-based research articles. Non-alcohol-related contributions included liver stiffness in HBV-induced hepatitis, Paneth cell-targeting for radiation-induced gut injury and β-catenin's role in hepatocellular carcinoma. A review article examined the impact of neutrophil extracellular traps (NETs) on NAFLD and potential therapeutic strategies. Immune responses are vital for mitigating damage and promoting tissue repair, but aberrant immune activation lead to chronic inflammation and organ dysfunction. This special issue highlights diverse contributions exploring immune dysregulation, offering insights into both alcohol-and non-alcohol-associated conditions.The highlight of the special issue is two human studies on Alcohol Use Disorder (AUD).The first, by Vatsalya et al., investigated the gut-brain axis, focusing on alcohol withdrawal, withdrawal-associated depression, and cravings. The study showed that patients with significant withdrawal symptoms exhibited elevated gut permeability markers, such as lipopolysaccharide (LPS) and soluble CD14 (sCD14), alongside increased adiponectin and proinflammatory cytokines (e.g., IL-6, IL-8). Adiponectin was significantly associated with withdrawal severity, reflecting its role in inflammation and metabolic signaling. Depression scores correlated with gut dysfunction and cytokine responses, while cravings were linked to decreased leptin and elevated inflammatory cytokines (IL-1β, TNF-α). This study also highlights sex differences, with women displaying heightened immune dysregulation and severe AUD symptoms, suggesting therapeutic targeting of gut-brain axis mechanisms.Building on this focus, the second human study, conducted by Sagaram et al., as key cytokines in differentiating and understanding the progression of alcoholic hepatitis (AH). IL-22 levels were elevated in AH patients compared to those with AUD without liver injury, correlating with liver injury markers (AST, AST:ALT ratio) and lifetime drinking history. IL-22 demonstrated antiinflammatory effects in non-severe AH subjects but became pro-inflammatory in subjects with severe AH, reflecting disease progression. IL-17 levels were highest with severe AH and correlated with MELD scores, indicating unresolved inflammation. These findings highlight IL-22 and IL-17 as key contributors to ALD progression, offering biomarkers and potential therapeutic targets for managing the disease.Extending the insights from the human studies to preclinical models, Yue et al., explored IL-22's protective mechanism in a preclinical model of AH. In mice, chronic alcohol exposure reduced intestinal IL-22 levels and impaired antimicrobial peptide (AMP) production and gut barrier integrity, leading to bacterial translocation and liver inflammation. IL-22 treatment however, effectively reversed these effects by restoring AMPs (e.g., Reg3, α-defensins), enhancing gut barrier proteins like ZO-1, and promoted the growth of beneficial microbiota such as Akkermansia spp. Additionally, IL-22 treatment improved liver histology, reduced lipid accumulation, and suppressed inflammatory cytokines via STAT3 activation in intestinal epithelial cells. These findings reinforce the potential of IL-22 as a therapeutic target for AH, demonstrating its role in gut-liver axis regulation and its relevance to human studies.Further complementing these studies, Meena et al., investigated the role of TRPV6, a calcium-permeable ion channel, in stress and corticosterone-mediated exacerbation of alcohol-induced gut barrier dysfunction and systemic inflammation in mice. Chronic alcohol feeding disrupted intestinal tight and adherens junctions, increased gut permeability, and led to endotoxemia, systemic inflammation, and liver damage in wildtype mice. These effects were reversed in TRPV6-deficient mice. TRPV6 deficiency also prevented alcohol and stress-induced intestinal dysbiosis. These findings identify TRPV6 as a key mediator of gut-liver axis disruption under alcohol and stress conditions, presenting it as a potential therapeutic target.Building molecular pathways in alcohol-induced gut-liver dysfunction, Walter et al.investigated the role of hepatocyte-specific mitogen-activated protein kinase phosphatase 1 (MKP1) in ALD. The study revealed that alcohol downregulated MKP1 expression, with females exhibiting greater susceptibility to liver injury. In MKP1-knockout mice, alcohol exposure led to severe liver damage, characterized by increased inflammation, endoplasmic reticulum stress (ER), and heightened c-Jun Nterminal kinase (JNK) activity, with these effects more pronounced in females. These findings emphasize MKP1's protective role in mitigating alcohol-induced liver injury and its potential as a therapeutic target to address sex-specific risks in ALD. In conclusion, this special issue highlights diverse research on immune modulation in alcohol-and non-alcohol-associated tissue injury, providing new insights into disease progression and potential therapeutic targets for liver and gastrointestinal diseases.