Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis Journal Article
| Authors: | Overstreet, A. M. C.; Burge, M.; Bellar, A.; McMullen, M. R.; Srivastava, V.; Czarnecki, D.; Huang, E.; Pathak, V.; Finney, C.; Vij, R.; Hunter, K. A.; Koff, B. B.; Dasarathy, S.; Dasarathy, J.; Streem, D.; Welch, N.; Rotroff, D.; Allende, D.; Schmitt, A. M.; Nagy, L. E.; Messer, J. S. |
| Article Title: | Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis |
| Abstract: | <p>Background:Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 [Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27] is a DAMP released from stressed cells, including hepatocytes. The goal of this study was to define the role of HSPB1 in AH pathophysiology.Methods:Serum HSPB1 was measured in a retrospective study of 184 healthy controls (HCs), heavy alcohol consumers (HA), patients with alcohol-associated cirrhosis (AC), and patients with AH recruited from major hospital centers.HSPB1 was also evaluated in liver tissue from HC and AH patients, existing RNA-seq data from ALD patient liver and monocytes, and livers from mice fed a Lieber-DeCarli diet. Cellular models of hepatocyte and macrophage interactions were used to evaluate the role of HSPB1 in inflammation during AH.Results:Circulating HSPB1 was significantly increased in AH patients, and levels positively correlated with disease-severity scores. HSPB1 was also increased in the livers of patients with severe AH and ethanol-fed mice. In cellular models, ethanol-stressed hepatocytes released HSPB1, which then triggered TNF alpha-mediated inflammation in macrophages. Anti-HSPB1 antibody prevented TNF alpha release from macrophages exposed to media conditioned by ethanol-stressed hepatocytes.Conclusions:Our findings support investigation of HSPB1 as both a biomarker and therapeutic target in ALD. Furthermore, this work demonstrates that anti-HSPB1 antibody is a rational approach to targeting HSPB1 with the potential to block inflammation and protect hepatocytes, without inactivating host defense.</p> |
| Keywords: | biomarker; heat shock protein 27; macrophage; macrophages; ethanol; expression; tumor-necrosis-factor; factor-alpha; hepatocellular-carcinoma; hsp27; tnf alpha; heat-shock-protein-27; hepatocyte; liver-injury; alcohol-associated liver disease |
| Journal Title: | Hepatology Communications |
| Volume: | 9 |
| Issue: | 9 |
| ISSN: | 2471-254X |
| Publisher: | John Wiley & Sons |
| Date Published: | 2025-09-01 |
| Start Page: | e0768 |
| Language: | English |
| ACCESSION: | WOS:001560187300001 |
| DOI: | 10.1097/hc9.0000000000000768 |
| PROVIDER: | wos |
| PMCID: | PMC12401206 |
| PUBMED: | 40879491 |
| Notes: | Article -- Source: Wos |
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