From phagocyte diversity and activation to probiotics:Back to Metchnikoff

Alberto Mantovani1,2

1 IRCCS Istituto Clinico Humanitas, Milan, Italy2 Institute of General Pathology, University of Milan, Milan, Italy

In this issue of the European Journal of Immunology, Siamon Gordon gives a detailed

account of Metchnikoff’s life and his achievements (Eur. J. Immunol. 2008. 38: 3257–3264).

Looking back at the roots of innate immunity stimulates reflections on open issues in the

field. Here, I give a personal view of some of these issues, including myeloid-derived

suppressor cells, macrophage polarization and adaptive responses of mononuclear

phagocytes.

Key words: Macrophage activation � Macrophages � M1/M2 polarization � Probiotics

See accompanying article by Gordon

Introduction

In his scholarly review [1], Siamon Gordon tracks the roots of

innate immunity to Elie Metchnikoff. The essay provides a

fascinating insight into Metchnikoff’s scientific life and how he

tackled fundamental issues in science, some of which remain with

us to this day. The perspective offered by a major player in the

very same field of phagocytes and innate immunity [2, 3] adds

flavour and fascination to this article not necessarily present in

other accounts [4]. Such a reflection on a central part of modern

immunology stimulates consideration of remaining open issues

and there follows a personal view of some of these.

Phagocyte heterogeneity: Frommicrophage–macrophage dichotomy tomyeloid-derived suppressor cells

The fundamental distinction between polymorphonuclear

leukocytes (microphages) and mononuclear phagocytes

(macrophages) was a major first step in the dissection of

phagocyte heterogeneity and lineage differentiation. The identi-

fication of myeloid-derived suppressor cells (MDSC) [5–7] raises

the questions whether the classic sharp distinction between the

myeloid and the monocyte–macrophage differentiation and

activation pathways is appropriate. In contrast to long-held

views, neutrophils express specific transcriptional programmes in

response to environmental signals [8]. MDSC include immature

myeloid precursors that can further differentiate, and play a key

role in the suppression of adaptive immunity in diverse

pathological conditions ranging from cancer to chronic infections

[5–7]. Are we dealing with a blurring of a classic distinction or

with a well-defined third phagocyte population? Using current

identification and separation criteria (e.g. Gr1, CD11b, F4/80)

MDSC in the blood and lymphoid organs are a mixed population,

which includes myeloid cells at different stages of differentiation

and mononuclear phagocytes. Thus, the definition of MDSC

remains an operational one rather than that of a cell type, a

reality that is frequently neglected. The issue of lineage of the

actual effectors of MDSC-mediated suppression is even more

relevant when their recruitment and activation in non-lymphoid

tissues is considered. For instance, do MDSC retain an immature

phenotype in tumour tissues or do they differentiate into tumour-

associated macrophages [9–11]? How do MDSC relate to

monocyte and macrophage subsets or differentiation stages, such

as the Tie2+ monocytes [12], tumour-associated macrophagesCorrespondence: Professor Alberto Mantovanie-mail: alberto.mantovani@humanitas.it

& 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

Eur. J. Immunol. 2008. 38: 3269–3273 DOI 10.1002/eji.200838918 HIGHLIGHTS 3269C

om

men

tary

and, more generally, polarized M2 macrophages [13]? Limited

profiling data on conventional MDSC suggest a definite relation-

ship with polarized M2 cells [14, 15]. More ‘‘omics’’ data coupled

with a focus on tissues may eventually solve some of these

unresolved questions. For the time being, I surmise that cells

belonging to the monocyte–macrophage lineage are the main

effectors of the MDSC phenomenology.

Activation and adaptive responses ofmacrophages

As discovered by Metchnikoff and described in Siamon Gordon’s

review [1], macrophages undergo activation in response to

environmental signals, including microbial products and cyto-

kines. Diversity is a hallmark of mononuclear phagocytes [2, 3]

and the same applies to the various forms of macrophage

activation [16–21] (Fig. 1). In response to some bacterial

moieties (e.g. LPS) and IFN-g, macrophages undergo classic (or

M1) macrophage activation. Selected properties of these cells

include production of copious amounts of reactive nitrogen and

oxygen intermediates and IL-12 [2, 16]. M1-activated macro-

phages are part of the polarized Th1 responses and are oriented

to mediate resistance against intracellular parasites and tumours

and to elicit tissue disruptive reactions. Alternative (or M2)

macrophage activation was originally discovered as a response to

IL-4 [2, 16]. M2-activated macrophages come in different

flavours depending on the eliciting signals, such as IL-4/IL-13,

immune complexes and ligands (IL-1 or LPS), acting through

receptors that involve downstream signalling through MyD88),

glucocorticoid hormones and IL-10. M-CSF-cultured monocytes

have a transcriptional profile close to IL-4-activated cells [22–24]

suggesting that this is a default pathway of differentiation. In

general, M2-activated cells share high expression of scavenger,

mannose and galactose receptors, and have an IL-12low, IL-10high,

IL-1 decoyRhigh, IL-1rahigh phenotype. They also have a distinct

chemokine expression pattern (e.g. CCL17 and CCL22 for M2

cells). Indeed the ‘‘chemokinome’’ is a major distinguishing

feature of the different forms of macrophage activation [22].

Macrophage polarization is also characterized by profound

effects on various metabolic pathways [22]. Iron metabolism,

as an example, is regulated at multiple steps differently affected

by polarizing cytokines, with M1 cells being characterized by

increased iron uptake and intracellular retention of the metal,

and M2 cells releasing iron in the extracellular milieu. The

cytokine regulation of iron metabolism in macrophages is a

crucial bacteriostatic mechanism and a key element in the

pathogenesis of anemia of chronic disease [25].

The various forms of M2 activation are oriented to the

promotion of tissue remodelling and angiogenesis, parasite

encapsulation, regulation of immune responses, as well as

promotion of tumour growth. Recent results have highlighted the

integration of M2-polarized macrophages with immuno-

regulatory pathways (Fig. 1). M2 cells were shown to induce

differentiation of regulatory T cells [26]; conversely, regulatory

T cells have been reported to induce alternative activation

of human mononuclear phagocytes [27]. While general

properties are retained from mouse to man, there are significant

CytokinomeCytokinome

Parasiteencapsulation

Tissueremodeling

Tumorpromotion

Immuno-regulation

Tissuedamage

Intracellularpathogens

Tumorresistance

MDSC

Tie2+

RNI

arginase -1

chitinase

M1M1 M2M2

IL-4/IL-13; IC/MyD88; IL-10; IL-21CSF-1; TGF-

bacteria; chronic virus; parasites; cancer

eg IL-1ra ; IL-1 decoy R

e.g. IL-1

ChemokinomeChemokinome

eg CCL22

e.g. CXCL10

Growth factorsGrowth factorsVEGF

+

+

Treg

SR, MR, GR

/Activin; γ γ Rays ;IFN- γ γ LPS

Figure 1. Diversity and polarization of macrophage activation: a continuum and a galaxy. In response to different signals (e.g. IFN-g and IL-4),macrophages undergo different forms of activation, from M1 (classic) to M2 (alternative). Only selected functions and representative molecules arepresented. The figure conveys the message that polarized M1- and M2-activated macrophages are the extremes of a continuum. It also underliesthat M2 activation is a galaxy elicited by diverse signals with core shared properties. SR, GR, MR: scavenger, galactose, mannose receptor; RNI,reactive nitrogen intermediates; IL-1ra, IL-1 receptor antagonist; IL-1 decoy R, type II IL-1 decoy receptor; immune complexes (IC).

Eur. J. Immunol. 2008. 38: 3269–3273Alberto Mantovani3270

& 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

differences, such as the association of YM1, Fizz1 and Arginase 1

with M2 polarization in the mouse but not in man [18].

In vivo counterparts of M2 macrophage polarization have

been observed in tissue remodelling during ontogenesis [28],

chronic inflammation [29–42], cancer [9, 12, 16, 17], bacterial

[43–49] and parasitic [50–53] infections. Evidence has also

accumulated that polarized macrophages are more than mere

spectators of immunopathology [35–41, 50–52].

The macrophage polarization paradigm, with M1 and M2 cells

mirroring the Th1 and Th2 lymphocytes, and classic cytokines

IFN-g and IL-4 respectively, as the main source of the

inducing signals, has had heuristic value; however, one should not

forget that this is an oversimplification, albeit a very useful one,

with intrinsic limitations. First, fully polarized macrophages are

the end of a continuum (Fig. 1). Second, cells sharing M2 prop-

erties are diverse depending on the in vitro or in vivo signals they

encounter. Third, activated macrophages are not amenable to

clonal analysis, a fundamental definition of T-cell subsets.

Fourth, the relationship between polarized macrophages and

monocyte subsets remains unclear [54]. For instance, functional

and profiling data suggest a similarity between the Tie2+ mono-

cytes and M2-polarized macrophages [12], but that does not

imply a continuum of differentiation. In general, the plasticity of

mononuclear phagocytes in response to environmental signals

highlights how, in fact, innate responses have a prominent

adaptive component [55].

From phagocyte biology to the bedside

Impressive progress has been made in the elucidation of

phagocyte differentiation and activation and in defining general

paradigms of function. In parallel, studies have highlighted the

key role of myelomonocytic cells in pathology from athero-

sclerosis to parasitic infections. Yet, translation into therapeutic

strategies of paradigms of macrophage plasticity and molecules

associated with it has lagged behind. For instance, we learn from

Siamon Gordon’s account about Metchnikoff’s interest and

obsession with the gut flora and Metchnikoff’s support for the

use of lactobacilli. Probiotics are currently enjoying the limelight

both from scientists and lay people, with new evidence from

double-blind clinical trials supporting their usage for medicinal

purposes [56]. Can we exploit the adaptive potential of

macrophages to shape resistance to pathogens and degenerative

diseases? Probiotics, of which Metchnikoff was a forerunner,

highlight a challenge for the innate immunity student, i.e.

translating better understanding of the biology of the adaptive

responses of phagocytes to the bedside.

Acknowledgements: A.M. is supported by Associazione Italiana

per la Ricerca sul Cancro (AIRC), Fondazione Cariplo, EC

Innochem Project, Telethon, Ministero Salute. I thank Paola

Allavena, Massimo Locati and Antonio Sica for invaluable

discussion.

Conflict of interest: The author declares no financial or

commercial conflict of interest.

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Abbreviation: MDSC: myeloid-derived suppressor cells

Full correspondence: Professor Alberto Mantovani, IRCCS Istituto Clinico

Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy

Fax: +39-02-82245101

e-mail: alberto.mantovani@humanitas.it

See accompanying article:

http://dx.doi.org/10.1002/eji.200838855

Received: 19/9/2008

Revised: 7/10/2008

Accepted: 13/10/2008

Eur. J. Immunol. 2008. 38: 3269–3273 HIGHLIGHTS 3273

& 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu