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Inflammation is highlighted as an initial factor that helps orchestrate liver reconstitution. However, the precise mechanisms controlling inflammation during liver reconstitution have not been fully elucidated. In this study, a clear immune response is demonstrated during hepatic reconstitution. Inhibition of the hepatic inflammatory response retards liver regeneration. During this process, Ccl2 is primarily produced by type 1 innate lymphoid cells (ILC1s), and ILC1‐derived Ccl2 recruits peripheral ILC1s and regulatory T cells (Tregs) to the liver. Deletion of Ccl2 or Tregs exacerbates hepatic injury and inflammatory cytokine release, accelerating liver proliferation and regeneration. The adoption of Tregs and IL‐10 injection reversed these effects on hepatocyte regenerative proliferation. Additionally, Treg‐derived IL‐10 can directly induce macrophage polarization from M1 to M2, which alleviated macrophage‐secreted IL‐6 and TNF‐α and balanced the intrahepatic inflammatory milieu during liver reconstitution. This study reveals the capacity of Tregs to modulate the intrahepatic inflammatory milieu and liver reconstitution through IL‐10‐mediated macrophage polarization, providing a potential opportunity to improve hepatic inflammation and maintain homeostasis. [ABSTRACT FROM AUTHOR]

Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms. [Display omitted] • An expansion of fragile-like Tregs is identified in heroin-associated blood • Opioid-induced global hypoxia triggers Treg fragility • Fabp7 protects BBB integrity from opioid-induced hyperpermeability • IFN-γ regulates opioid-induced NAc synaptic remodeling and withdrawal signs Opioids drive the peripheral expansion of fragile-like regulatory T cells that cross the blood-brain barrier and, through IFN-γ, mediate synaptic instability and subsequent withdrawal symptoms. [ABSTRACT FROM AUTHOR]