Abstract

   Chronic liver diseases are highly linked with mitochondrial dysfunction
   and macrophage infiltration. Mallory-Denk bodies (MDBs) are protein
   aggregates associated with hepatic inflammation, and MDBs pathogenesis
   could be induced in mice by feeding
   3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Here, we investigate
   the macrophage heterogeneity and the role of macrophage during MDBs
   pathogenesis on DDC-induced MDBs mouse model by single-nucleus RNA
   sequencing (snRNA-seq). We defined liver macrophages into four distinct
   subsets including monocyte-derived macrophages (MDMs) subset and three
   Kupffer cells (KCs) subsets (Gpnmb^high KCs, Peam1^high KCs, and
   Gpnmb^low Pecam1^low KCs). Particularly, we identified a novel
   Gpnmb^high KCs subset as lipid-associated macrophage (LAM) with high
   expression of Trem2, CD63, and CD9. Interestingly, LAM showed a
   potential immunosuppressive characteristic by expressing
   anti-inflammatory genes IL-7R during the MDBs formation. Using contact
   and transwell co-culture systems, the released mtDNA from hepatocytes
   was found to induce the activation of inflammasome in macrophages.
   Furthermore, we revealed the damaged DNA could activate the NOD-like
   receptor family pyrin domain containing-3 (NLRP3) inflammasome and
   subsequently form apoptosis-associated speck-like protein containing a
   caspase recruit domain (ASC) specks of liver macrophages. Collectively,
   our results firstly revealed macrophage heterogeneity and inflammasome
   activation by mtDNA from injured liver during MDBs pathogenesis,
   providing crucial understanding of pathogenesis of chronic liver
   disease.

Supplementary Information

   The online version contains supplementary material available at
   10.1186/s12967-024-05999-7.

   Keywords: Mallory-denk bodies (MDBs), Lipid-associated macrophage,
   Single-nucleus RNA-sequencing, mtDNA, Inflammasome

Introduction

   Mallory-Denk bodies (MDBs) are protein aggregates described as the
   morphological feature of alcoholic steatohepatitis (ASH) and
   non-alcoholic steatohepatitis (NASH), the pathogenesis of which has
   also been linked to cellular stress and aging [[38]1–[39]3]. Similarly,
   the formation of MDBs-like cytoplasmic inclusions also occurred in
   neurodegenerative diseases such as Alzheimer’s, Parkinson’s and
   Desmin-related myopathies [[40]4]. MDBs are the inclusions commonly
   seen in hepatocellular carcinoma (HCC), therefore the acknowledgment of