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Macrophages are cells of the immune system most

well- known for their ability to engulf big particles, to

which they owe their name from the Greek makrós

phagein (large eaters). They are present in essentially

all organs of the body from embryonic to adult life

Macrophages are highly plastic cells that sense, react and

respond to their surrounding and systemic environment

by changing their function, morphology and phenotype

During immune activation, macrophages have a crucial

role both in the innate, rapid, non- specific defence res-

ponses, and in the long- lasting and specific adaptive

responses that involve the recruitment of other immune

cells

. In addition to their phagocytic capacity, macro-

phages produce a plethora of factors such as cytokines,

chemokines and growth factors, which are involved in

the responses to infection and in tissue repair. In addi-

tion to their immunoregulatory roles in tissue homeo-

stasis and defence against pathogens, macrophages limit

the development of various diseases including sepsis,

chronic inflammatory diseases (such as rheumatoid

arthritis, colitis and psoriasis), neurodegenerative dis-

eases and cancer

. In the past two decades, macrophages

have also been extensively studied for their contribution

to metabolic diseases, such as obesity- associated insulin

resistance and diabetes mellitus.

The liver is an important metabolic organ in which

macrophages reside and serve as a first line of defence

against material from the gastrointestinal tract that

passes through the liver via the portal circulation. While

the liver is often described as the organ with the highest

proportion of macrophages

, this interpretation of the

available literature is difficult to confirm as methods

of macrophage extraction and subsequent analysis

can greatly interfere with their recovery and identifi-

cation. It is nevertheless clear that the liver contains a

substantial number of macrophages, which contribute

to both its maintenance and its function

. Changes in

the dynamics of liver macrophage turnover and func-

tion have been described in non- alcoholic fatty liver

disease (NAFLD)

5,6

In this Review, we discuss the role of liver macro-

phages in steady state and in obesity- associated metab-

olic diseases, such as insulin resistance and NAFLD.

We particularly concentrate on data generated using

single- cell RNA sequencing (scRNA- seq) and focus on

both the inflammatory and non- inflammatory roles of

macrophages in the development of obesity- associated

metabolic impairment in mice and humans. Finally, we

use an integrated approach to present the similarities

and discrepancies among scRNA- seq analyses aimed to

Macrophage functional diversity in

NAFLD — more than inflammation

EmelieBarreby , PingChen and MyriamAouadi

✉

Abstract

Macrophages have diverse phenotypes and functions due to differences in their

origin, location and pathophysiological context. Although their main role in the liver has

been described as immunoregulatory and detoxifying, changes in macrophage phenotypes,

diversity, dynamics and function have been reported during obesity- related complications

such as non- alcoholic fatty liver disease (NAFLD). NAFLD encompasses multiple disease

states from hepatic steatosis to non- alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and

hepatocarcinoma. Obesity and insulin resistance are prominent risk factors for NASH, a disease

with a high worldwide prevalence and no approved treatment. In this Review, we discuss the

turnover and function of liver- resident macrophages (Kupffer cells) and monocyte- derived

hepatic macrophages. We examine these populations in both steady state and during NAFLD,

with an emphasis on NASH. The explosion in high- throughput gene expression analysis using

single- cell RNA sequencing (scRNA- seq) within the last 5 years has revolutionized the study of

macrophage heterogeneity, substantially increasing our understanding of the composition and

diversity of tissue macrophages, including in the liver. Here, we highlight scRNA- seq findings from

the last 5 years on the diversity of liver macrophages in homeostasis and metabolic disease, and

reveal hepatic macrophage function beyond their classically described inflammatory role in the

progression of NAFLD and NASH pathogenesis.

Center for Infectious

Medicine, Department

of Medicine Huddinge,

Karolinska Institutet,

Karolinska University

Hospital, Stockholm,

Sweden.

✉

e- mail: Myriam.aouadi@

ki.se

https://doi.org/10.1038/

s41574-022-00675-6

REVIEWS

NAtuRe RevIews

ENDoCRiNoLoGy VOLUME 18

AUGUST 2022

461

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define liver macrophage populations and propose future

directions to achieve harmony of studies in both mice

and humans.

Physiological liver macrophage dynamics

Liver macrophages consist of tissue- resident Kupffer

cells and recruited monocyte- derived macrophages from

the systemic circulation

7,8

. Liver macrophages typically

reside on the luminal side of the liver sinusoids, partly

protruding into the perisinusoidal space where they are

in close contact with hepatic stellate cells

. Liver macro-

phages are involved in tissue remodelling, responses to

gut-derived pathogens, regulation of hepatocyte metab-

olism, iron and cholesterol metabolism and maintenance

of immunological tolerance in the liver

7,10

. A 2017 study

also identified a distinct subset of monocyte- derived

macrophages (liver capsular macrophages) that reside

in the hepatic capsule and function to protect the liver

from pathogens derived from the peritoneum

Turnover of mouse liver macrophages

Fate mapping studies in mice have been crucial in eluci-

dating the turnover of liver macrophage subsets. These

studies have shown that the majority (95%) of resident

liver macrophages are Kupffer cells, which are derived

from embryonic precursors from the

yolk sac or the

fetal liver

12,13

. Kupffer cells are seeded before birth and

maintained by local proliferation, independently of the

recruitment of bone marrow- derived circulating mono-

cytes at steady state

4,14–16

. The proliferation of Kupffer

cells occurs when there is a need for replenishment of

liver macrophages. This process occurs through the

transient downregulation of the transcription factors

MafB and c- Maf, which repress macrophage-specific

enhancers associated with a gene network that controls

self- renewal

Due to the large volume of blood that is continu-

ously passing through the liver, the liver is highly acces-

sible to monocytes from the systemic circulation that

can enter and expand the pool of liver macrophages

during conditions such as inflammation and metab-

olic disease or following Kupffer cell depletion

8,18

However, these monocytes only differentiate into

macro phages and gain tissue- specific functions when a

niche is available

. In mice, circulating monocytes can

be divided into two subsets: inflammatory monocytes

and patrolling monocytes. The latter are monocytes

that are recruited to non- inflamed tissues expressing

Ly6C

low

(CXCR1

high

CCR2

−

CD62L

−

CD43

high

) and mainly

function to patrol the vasculature and healthy tissues.

Inflammatory monocytes are short-lived cells

expressing Ly6C

high

(CX

CR1

mid

CCR2

CD62L

CD43

low

and they respond to inflammatory signals such as mono-

cyte chemoattractant protein 1 (MCP1, also known as

CCL2), by migrating to the site of inflammation and

differentiating into monocyte- derived macrophages

and monocyte- derived dendritic cells

20–22

. Upon recruit-

ment to the liver, inflammatory monocytes can acquire

a similar phenotype to resident Kupffer cells when an

empty niche is available

8,23

The local tissue environment is important in shap-

ing the phenotype of recruited macrophages, as speci fic

signals from the liver niche drive the development and

maintenance of resident monocyte- derived macro phages

during homeostasis

9,24

. However, not all infiltrating

monocytes differentiate into long- lived resident macro-

phages, and, in some instances (for example, during

inflammation or loss of resident macrophages), recruited

monocytes differentiate into short- lived macro phages

that only temporarily reside in the liver

9,25,26

. Moreover,

mature peritoneal cavity macrophages (expressing

F4/80

GATA6

) have previously been shown to infiltrate

the liver upon

sterile injury, where they then acquire a

restorative phenotype

. However, this finding is cur-

rently debated as another study demonstrated that,

although peritoneal macrophages accumulate on the liver

surface in response to injury, they do not invade the

liver tissue

. Taken together, these studies have, however,

demonstrated that recruited liver macrophages can arise

from different sources and that their fate depends on

their origin and localization

(FIG.1).

Turnover of human liver macrophages

While the ontogeny and replenishment of liver macro-

phages have been extensively studied in mouse

models

12,16,17

, little is known about the origin and replen-

ishment of their human counterparts. In humans, circu-

lating monocytes are classified by expression of either

CD14

CD16

low

(classic monocytes), CD14

CD16

(intermediate monocytes) or CD14

low

CD16

(non-

classic monocytes)

29,30

. Classic monocytes are short- lived

cells (1–2 days) that make up 85% of all circulating

monocytes, and are thought to be the main source of both

CD14

CD16

intermediate monocytes and monocyte-

derived macrophages in tissues

31,32

. Human clas-

sicmonocytes, corresponding to inflammatory Ly6C

high

monocytes in mice, are maintained in reserves in the

bone marrow and spleen at steady state, where they

are readily available upon infection or injury. Non-

classic monocytes, the counterpart to patrolling Ly6C

low

monocytes in mice, reside for longer in the circulation

where they patrol and are involved in maintaining tissue

homeostasis. Intermediate monocytes do not patrol the

vasculature; however, they share characteristics of both

classic and non- classic monocytes

. Although studies

have shown that human monocytes can infiltrate into

tissues during inflammation

33–35

, similar to monocytes in

mice, the fate of these cells after the resolution of inflam-

mation is unclear. Additionally, it is not currently known

Key points

•Macrophages are highly plastic cells of the immune system that can acquire a

spectrum of phenotypes according to their spatiotemporal pathophysiological

context.

•Liver macrophages are either embryo- derived resident macrophages or recruited

peripheral monocyte- derived macrophages.

•Liver macrophages have been shown to contribute to non- alcoholic fatty liver

disease (NAFLD) progression in obesity through production of both inflammatory

and non- inflammatory factors.

•Single- cell RNA sequencing (scRNA- seq) has identified distinct liver macrophage

subsets in mice and humans in health and liver disease.

•scRNA- seq has enabled the identification of novel pathogenic factors expressed

by liver macrophages that could exacerbate or protect from NAFLD progression.

Fate mapping

Labelling of specific cell

subsets in the embryo to

trace their contribution

to cell populations and

tissues in the adult organism.

Yolk sac

A sac attached to the embryo

during development that

provides nutrients and cells

to the embryo.

Sterile injury

Injury or inflammation

not caused by pathogenic

infection.

www.nature.com/nrendo

Reviews

462

AUGUST 2022

VOLUME 18

of 12

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