from phagocyte diversity and activation to probiotics: back to metchnikoff
TRANSCRIPT
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: [email protected]
& 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: [email protected]
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