Regression-associated macrophages license neutrophils to exacerbate rechallenge liver injury

Background and Aims Chronic liver injury leads to pronounced immune alterations, but the persistence of these changes after regression and the impact of immunological reprogramming on the response to subsequent injury remain uncertain. Patients with chronic liver diseases suffer from phases of high disease activity followed by months of regression. Methods Here we used a mouse model of chronic liver toxicity, followed by regression, and re-injury. Through the utilization of monocyte fate-mapping tools, intravital imaging, linage-specific depletion and single-cell sequencing, we tracked macrophages from different origins and analyzed the alterations in their phenotype and function. Results We found that while liver damage returned to normal levels during regression, rechallenge with a single dose resulted in exacerbated liver damage compared to both acute and chronic injury. Chronic injury profoundly reprogrammed the hepatic macrophage compartment, leading to the emergence of a distinct population of regression-associate macrophages (RAMs) during restoration. These RAMs were identified by CD9 and TREM-2 expression, contained abundant TNFα and engaged in frequent and prolonged interactions with neutrophils. Single-cell sequencing unveiled a prominent “neutrophil recruitment” signature in RAMs and effector cytokines such as TNFα in neutrophils. Genetic depletion of RAMs, antibody-mediated blockade of TNFα or Ly6G, effectively alleviated the exacerbated liver damage following re-challenge. Conclusion Our findings identify long-lasting macrophage reprogramming as a key contributor to aggravated liver injury through TNFα secretion and neutrophil activation, providing new insights into potential therapeutic strategies for severe liver diseases such as alcohol-associated hepatitis and acute on chronic liver failure. Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany