COMMD10 is critical for Kupffer cell survival and controls Ly6Chi monocyte differentiation and inflammation in the injured liver.

Noam Erez,Marva Langer,Chen Varol,Daniel J Kedar,Helen S Goodridge,Nathan Gluck,Itay Moshkovits,Anat Neumann,Martin Guilliams,Shani Ben Shlomo,Eli Brazowski,Rotem Pelet,Keren Cohen,Odelia Mouhadeb

doi:10.1016/j.celrep.2021.110026

Abstract

Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.

Highlights

Most tissue-resident macrophages are established prenatally and self-maintain independently of bone marrow (BM) monocytes
COMMD10 is required for homeostatic maintenance of Kupffer cells (KCs) To target COMMD10 deficiency to KCs we crossed Clec4f+/cre mice (Scott et al, 2018) with Commd10fl/fl mice (Mouhadeb et al, 2018) (Clec4fDCommd10)
Commd10 gene expression decreased by about 50% in Clec4fDCommd10 KCs (Figure 1A)

Summary

Introduction

Most tissue-resident macrophages are established prenatally and self-maintain independently of bone marrow (BM) monocytes. Kupffer cells (KCs) dominate the homeostatic macrophage pool They reside in the sinusoidal vessels and in the space of Disse, interacting with hepatic stellate cells (HSCs) and hepatocytes (Bonnardel et al, 2019), where they act as sentinels and perform specialized accessory functions involving iron and lipid metabolism (Scott and Guilliams, 2018). Resident KCs (ResKCs) are replaced by BM Ly6Chi monocyte-derived KCs (MoKCs) that adopt ResKC functions during homeostasis and disease (Bonnardel et al, 2019; Remmerie et al, 2020; Sakai et al, 2019; Scott et al, 2016; Seidman et al, 2020; Tran et al, 2020). While the impact of Ly6Chi monocyte bifurcation on liver diseases

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Discussion

Conclusion