ARTICLE IN PRESS

Immunobiology 214 (2009) 630–641

0171-2985/$ - se

doi:10.1016/j.im

Abbreviations

antigen; IRS, in

monocyte chem

oxide; PI3K, ph�CorrespondE-mail addr

www.elsevier.de/imbio

REVIEW

Alternative activation of macrophages: Immune function and

cellular biology

Audrey Varin, Siamon Gordon�

Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

Received 14 November 2008; accepted 14 November 2008

Abstract

Macrophages are the first line of defense of the organism against pathogens and, in response to themicroenvironment, become differentially activated. In the presence of IL-4 and IL-13, cytokines that are producedin a Th-2 type response, particularly during allergy and parasitic infections, macrophages become differentiallyactivated. Alternative activated macrophages play an important role in the protection of the host by decreasinginflammation and promoting tissues repair. However, alternative activation of macrophages also downregulates hostprotection against selected pathogens. This defect is associated with an altered receptor expression pattern andextensive modulation of intracellular membrane trafficking. This review shows how alternative activation ofmacrophages induces extensive cellular remodelling of phagocytic, endocytic, signaling and secretory pathways whichplay an important, but unclear role in the pathogenesis of different disease.r 2009 Elsevier GmbH. All rights reserved.

Keywords: Alternative activated macrophages; Endocytosis; IL-4; Immune functions; Membrane traffic; Signal transduction

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630

IL-4-induced signal transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

Anti-inflammatory effects of IL-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632

Role of IL-4 in host defense to infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

Effect of alternative activation on macrophage membrane functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

e front matter r 2009 Elsevier GmbH. All rights reserved.

bio.2008.11.009

: AAMF, alternative activated macrophages; Ag,

sulin receptor substrates; JAK, janus kinase; MCP-1,

otactic protein 1; MR, mannose receptor; NO, nitric

osphoinositide-3-kinase.

ing author. Tel.: +44 1865 275 500.

ess: siamon.gordon@path.ox.ac.uk (S. Gordon).

Introduction

Macrophages play a crucial role in innate andadaptative immunity in response to microorganisms andare major mediators of the inflammatory response. Duringinfection, macrophage effector functions are critical for the

ARTICLE IN PRESSA. Varin, S. Gordon / Immunobiology 214 (2009) 630–641 631

elimination of pathogens, however uncontrolled inflam-matory responses can induce injury of the tissue environ-ment and must be repressed to allow the process of repair.Therefore the disease stage, tissue and cytokine micro-environment induce, in vivo, a heterogeneous macrophagepopulation that displays an appropriate inflammatoryphenotype (Gordon and Taylor, 2005). In vitro, two majormacrophage populations are characterized. Classicallyactivated or type I macrophages, induced in particularby IFNg (Dalton et al., 1993), display a pro-inflammatoryprofile whereas alternatively activated or type II macro-phages (AAMF), induced by Th-2 cytokines, express anti-inflammatory and tissue repair properties (Gordon, 2003).

In this review, we summarize the effects of IL-4-inducedalternative activation on macrophages with special refer-ence to altered immune functions and cellular biology.

IL-4-induced signal transduction

Alternative activation of macrophages is induced byIL-4 and IL-13, cytokines that are produced in a Th-2

IL-4

JAK-3P

PPP

Shp-1

STAT6 P

STAT6 P

IL-4 responsive genesMHC class II CD23IL- 4Rαα Igε

STAT6protease

STAT6

STAT6

P

P

STAT6

STAT6

P

P

STAT6

STAT6

JAK-1

IRS-1/2

Shc

NUCLEUS

CYTOPLASM

IL-2

Rγc

IL-4

Rα

Fig. 1. IL-4 receptor signaling. IL-4 mediates the heterodimerisation

JAK kinase family inducing the phosphorylation of the cytoplasmic

of interaction with signaling molecules inducing different pathw

phosphorylated domain of the IL-4R, is phosphorylated and leaves

STAT-6. The complex translocates to the nucleus and binds to promo

IRS-1/2, inducing proliferative responses via the PI3K and Ras-MA

type response, particularly during allergic, cellular andhumoral responses to parasitic and selected pathogeninfections. IL-4 is a pleiotropic type I cytokine producedby a subpopulation of CD4+ T cells, designated Th-2cells, and by basophils and mast cells. IL-4 modulatesother lymphoid cell activities such as regulation of thedifferentiation of antigen-stimulated T lymphocytes(Hsieh et al., 1992; Seder et al., 1992) and control ofimmunoglobulin class switching in B lymphocytes(Coffman et al., 1986; Gascan et al., 1991; Vitettaet al., 1985).

The signaling pathway induced by IL-4 depends uponexpression of IL-4 receptors (IL-4R) (Fig. 1). IL-4mediates heterodimerisation of the IL-4Ra chain with asecond chain. The gamma common chain (gc) appearsto be the dominant chain involved in heterodimerizationof the receptor, but the IL-4Ra chain can also functionas a component of the IL-13 receptor (Miloux et al.,1997; Murata et al., 1998; Obiri et al., 1995, 1997).

The IL-4Ra chain is a member of the hematopoietinreceptor superfamily, sharing structural motifs in theextracellular region (Miyajima et al., 1992). These motifs

IRS-1/2

S

G2M

G1 CELLCYCLE

IRS-1/2 Grb2PI3K

Growthpathway

p70s6K PKB

HMG(I)Y

Anti-apoptoticpathway

of the IL-4Ra with IL-2Rg chain and activates members of the

domain of the IL-4R. The phosphorylated tyrosines are the site

ays like the Jak/STAT-6 pathway. STAT-6 binds to the

the receptor to form a homodimer with a second molecule of

ters of IL-4 responsive genes. Another pathway is mediated by

PK signaling pathways.

ARTICLE IN PRESSA. Varin, S. Gordon / Immunobiology 214 (2009) 630–641632

include conserved paired cysteine residues and, in themembrane proximal region, a WSXWS motif requiredfor the conformation of the receptor chain that mediatesspecific cytokine binding (Livnah et al., 1996).

IL-4R requires receptor-associated kinases for initia-tion of the signal. The members of the janus kinasefamily (JAK) JAK-1, JAK-2 and JAK-3, (Ihle, 1995;Taniguchi, 1995), are activated in response to IL-4stimulation and are associated with different compo-nents of the IL-4R (Johnston et al., 1994; Murata et al.,1995; Witthuhn et al., 1994). In addition to the JAKkinase family, the Src-kinase family has also been shownto interact with the IL-4R and to be activated after IL-4stimulation (Izuhara et al., 1993). Activation of thesedifferent kinases induces the phosphorylation of fiveconserved tyrosine residues in the cytoplasmic domainof the IL-4R. The phosphorylated tyrosines are the siteof interaction with signaling proteins via their Src-homology 2 (SH2) domain, inducing different pathways.One of these pathways is the JAK/STAT-6 pathwayinducing expression of IL-4 induced genes. IL-4Rengagement activates JAK-1 and JAK-3, inducing thephosphorylation of specific tyrosine residues in thecytoplasmic domain of the receptor. STAT-6 binds tothe phosphorylated domain of the receptor and isphosphorylated at a C-terminal tyrosine residue by theactivated kinases (Darnell, 1997; Velazquez et al., 1992).The phosphorylated STAT-6 leaves the receptor and

IL-4

1) UPTAKE-MEDIATED via IL-4 INCREASE RECEPTOR EXPRESSION

Galactose C-type lectin

3) ANTIMICROBIALACTIVITY

IL-4

+

Fcεε receptor

Scavenger receptors

Mannose receptor

NO

Fig. 2. Effect of IL-4 on cell biology of macrophages. AAMF are ch

which in turn affects endocytosis and phagocytosis (1). Moreover, A

with the stimulation of anti-inflammatory cytokines and inhibition

inflammation, AAMF down-regulate host protection against differe

forms homodimers with a second molecule of phos-phorylated STAT-6 through the C-terminal phospho-tyrosine residues. This complex translocates to thenucleus and binds to the promoter of IL-4 responsivegenes like MHC class II, IL-4R a chain, FcRe (Delphinand Stavnezer, 1995; Kaplan et al., 1996; Reichel et al.,1997; Ryan et al., 1996; Shimoda et al., 1996). IL-4 alsonegatively regulates this pathway by inducing thefeedback regulatory proteins, suppressors of cytokinesignaling (SOCS) (Dickensheets et al., 2007).

Another pathway of signal transduction is mediatedby IRS-1/2, inducing IL-4 mediated proliferative re-sponses. IRS1/2 binds to one of the phosphorylatedmotifs of the IL-4Ra chain. This interaction induces thephosphorylation of IRS1/2 via action of the receptor-associated kinase, like the JAK kinases. The phosphory-lated form of IRS1/2 interacts with downstreamsignaling molecules such as the regulatory sub-unit ofphosphoinositide-3-kinase (PI3K) and the adaptermolecule Grb-2. These interactions induce activationof the PI3K and Ras-MAPK signaling pathway.

Anti-inflammatory effects of IL-4

One of the main characteristics of AAMF is theiranti-inflammatory properties (Fig. 2, Tables 1 and 2).

2) INFLAMMATION ANDREPAIR

IL-4

+

Transferrin R

Anti-inflammatorycytokines

IL-27R

TREM2

CD163

Pro-inflammatorycytokines

aracterized by modification of the receptor expression profile,

AMF have anti-inflammatory and repair properties associated

of pro-inflammatory cytokines (2). In addition to reducing

nt pathogens via reduced NO production (3).

ARTICLE IN PRESS

Table 1. Effect of IL-4 on macrophage activity.

Role Reference

Tissue repair Increase of extracellular matrix

remodelling and fibrogenesis

Gratchev et al. (2001)

m Angiogenesis Goerdt et al. (1993), Kodelja et al. (1997)

Modulation of inflammation

� mAnti-inflammatory cytokines� kPro-inflammatory cytokines� Modulation of the IL-27R

Bonder et al. (1998), Cheung et al. (1990), Fenton et al.

(1992), Ruckerl et al. (2006), Schebesch et al. (1997), and

Turnbull et al. (2006)

Protection of the host from unwanted

inflammation during Pathology

� Placenta, lung� Rheumatoid arthritis� Psoriasis� Alzheimer’s disease� Autoimmune encephalomyelitis

Cao et al. (2007), Colton et al. (2006), Djemadji-Oudjiel

et al. (1996), Finnegan et al. (2002), Goerdt et al. (1993),

Ponomarev et al. (2007), and Szekanecz et al. (1994)

Ag presentation m MHCII expression Cua and Stohlman (1997) and de Waal Malefyt et al.

(1993)

Differentiation of naıve T cells

Antimicrobial activity Decreased NO production Gratchev et al. (2001), Hesse et al. (2001), and Munder et

al. (1998)

Inhibition of MCP-1 Ritter and Moll (2000)

Inhibition of Th-1 and Ab response

during Leishmaniasis

Holscher et al. (2006)

Table 2. Modulation of receptors after alternative activation of macrophages.

Receptors Expression modulated

by IL-4

Functions References

MR m Enhanced endocytosis Doyle et al. (1994) and Stein et al.

(1992)

MHC-II m Ag presentation de Waal Malefyt et al. (1993)

CD23 m Increased FceR uptake Becker and Daniel (1990)

TfR m Enhanced ferritin translation DeFife et al. (1997) and Weiss et al.

(1997)

TREM2 m Inhibition of cytokine production Turnbull et al. (2006)

IL-27Ra chain m Decreased immune response during

inflammation

Ruckerl et al. (2006)

Stabilin 1 m Uptake of SPARC and inhibition of

inflammation

Kzhyshkowska et al. (2006a, b)

CD163 k Noninflammatory response of macrophages to

haemoglobin

Porcheray et al. (2005)

RANKL k Inhibition of bone resorbtion Moreno et al. (2003)

E-cadherin k Promotion of Multinucleated Giant Cells

(MGC)

Moreno et al. (2007)

DC-STAMP m Promotion of MGC formation via

transcriptional activation

Yagi et al. (2007)

Dectin 1 m Binding and uptake of b glucan Willment et al. (2003)

Galactose C-type

lectins

m Recognition and uptake of glycoproteins and

cancer cells

Ichii et al. (2000) and Kawakami et

al. (1994)

A. Varin, S. Gordon / Immunobiology 214 (2009) 630–641 633

Accordingly, IL-4 stimulates the production of anti-inflammatory cytokines such as IL-10 and IL-1Rantagonist (Fenton et al., 1992; Schebesch et al., 1997)

and inhibits expression of the pro-inflammatorycytokines IL-1, TNFa, IL-6, IL-12 and MIP-1a,thus reducing inflammation (Bonder et al., 1998;

ARTICLE IN PRESSA. Varin, S. Gordon / Immunobiology 214 (2009) 630–641634

Cheung et al., 1990). Moreover, AAMF selectivelyincrease production of macrophage-derived chemokine(MDC) and thymus and activation-regulated chemokine(TARC), inducing recruitment of antigen presentingcells to the site of inflammation (Bonecchi et al., 1998;Mantovani et al., 2000). Turnbull et al. showed that IL-4induces TREM-2 expression in macrophages which, viaDAP-12 signaling, inhibits macrophage cytokine pro-duction and restrains macrophage activation (Turnbullet al., 2006). The regulation of inflammation by IL-4 isalso mediated by increased expression of the IL-27receptor a chain on macrophages. IL-27 seems to be animmunoregulatory cytokine; studies show that afterinfection with different pathogens, IL-27R�/� miceshowed T cell hyperactivation and an excess productionof pro-inflammatory cytokines (Hamano et al., 2003;Holscher et al., 2005; Villarino et al., 2003). IL-4collaborates with IL-27 and IL-10 in modulatingmacrophage activation by successive up-regulation ofIL-27Ra and IL-4Ra (for IL-10), in order to limit anexcessive immune response in inflammatory diseases(Ruckerl et al., 2006).

In parallel to the inhibition of inflammation AAMFare associated with tissue repair. The presence ofAAMF is characterized by an increase of extracellularmatrix remodeling, associated with the expression ofmatrix proteins such as fibronectin, bIGH3 andfibrogenesis and a high expression of arginase 1(Gratchev et al., 2001; Louis et al., 1999; Modolellet al., 1995; Munder et al., 1999). Arginase 1 hydrolyzesL-arginine to urea and L-ornithine which is used toproduce polyamines and proline to promote cellgrowth and collagen production (Fig. 3). AAMFmay contribute to the growth of epithelial cellsand to granulomatous fibrosis, allowing tissue repair.The presence of AAMF is also associated with ahigh degree of vascularization and with an increase

L-Arginine

Classical activation (IFN γ )

Alternative activation (IL-4)

Arginase 1

iNOS

L-ornithine

L-hydroxy-arginine

Fig. 3. IL-4 controls L-arginine metabolism in macrophages by mod

2001). Classically activated macrophages exhibit increased NOS act

production, contributing to their antimicrobial activity. By contrast

Here, L-arginine is metabolized to urea and L-ornithine which is m

proliferation, or proline, the basic building block of collagen, prom

of angiogenesis (Goerdt et al., 1993; Kodelja et al.,1997).

The important role of the AAMF in protection of thehost by negative regulation of inflammation has beenconfirmed by different in vivo studies. In the healthyhost, AAMF are found in normal placenta and lungwhere they serve to protect the respective organ fromunwanted inflammation and immune reactivity (Mueset al., 1989; Van den Heuvel et al., 1999). Moreover,AAMF have been identified during the repair phase ofan acute inflammation as well as in chronic inflamma-tory diseases such as rheumatoid arthritis (Goerdt et al.,1993). Different studies have demonstrated the protec-tive role of synovial macrophages during proteoglycan-induced arthritis by inhibition of pro-inflammatorycytokine and chemokine production, reducing inflam-matory cell infiltration into the joints (Cao et al., 2007;Finnegan et al., 2002). Moreover, recent studies showthat IL-4 increases expression of the scavenger receptorStabilin 1 which mediates the uptake and degradation ofSPARC (secreted protein acidic and rich in cysteine),leading to the proposal that AAMF resolve inflamma-tion and promote angiogenesis (Kzhyshkowska et al.,2006a, b). Ponomarev et al. showed that AAMFregulate inflammation of the central nervous system ina model of autoimmune encephalomyelitis (Ponomarevet al., 2007). However, AAMF are present in Alzhei-mer’s disease brain and may contribute to a Th-2-linkedpathology (Colton et al., 2006). Porcheray et al.confirmed the possible negative effect of AAMF bydecreasing CD163 expression on the macrophage sur-face (Porcheray et al., 2005), whereas other studieshave shown that CD163-expressing macrophages exertpositive effects during the healing phase of acuteinflammatory reactions, in chronic inflammatory dis-eases such as psoriasis and during wound healing(Djemadji-Oudjiel et al., 1996; Zwadlo et al., 1987).

Citrulline

NO

Polyamines →→ cell proliferation

Proline→ collagen production

ulating NOS/arginase 1 expression (adapted from Hesse et al.,

ivity, which promotes L-hydroxyarginine, L-citrulline, and NO

, AAMF show increased arginase and decreased NOS activity.

etabolized to produce polyamines, molecules that induce cell

oting tissue repair.

ARTICLE IN PRESSA. Varin, S. Gordon / Immunobiology 214 (2009) 630–641 635

Moreover, macrophages expressing CD163 play acentral role in hemoglobin clearance, which limitsoxidative heme toxicity, presumed to contribute to thepathogenesis of atherosclerosis (Jeney et al., 2002;Kristiansen et al., 2001; Rother et al., 2005; Schaeret al., 2006). Overall, these data show that the protectiverole of AAMF during inflammation is more complexand possibly less beneficial than we suppose.

Role of IL-4 in host defense to infection

In addition to their role in reducing inflammation andhost injury, many studies have shown that AAMFdown-regulate host protection against different patho-gens. AAMF do not display enhanced killing towardsmost microbes. Indeed, the production of microbicidalNO is counteracted by increased expression of arginase1 (Fig. 3) (Munder et al., 1998). Arginase 1 hydrolyzesL-arginine to urea and L-ornithine, but L-arginine alsoserves as the nitrogen source for the NOS (NO synthase)in the generation of NO. Competition for the samesubstrate by these two enzymes directly affects theability of host cells to induce nitrosative stress (Songet al., 2000). Some pathogens use this specificity to theirown advantage. Peteroy-Kelly et al. (2003) demon-strated that mycobacteria increase arginine transport ininfected macrophages and acquire the metabolitesrequired for bacterial growth and therefore inhibitcapacity of the macrophages to kill them. Moreover,AAMF decrease host protection by modulating theprotective immune system. IL-4-induced AAMF pro-mote Leishmania infection by inhibiting Th-1 andhumoral responses of the host and by suppressingmacrophage killing activity (Holscher et al., 2006). IL-4

0 + IL-4

Fig. 4. IL-4 induces giant cell formation via macrophage

fusion (Helming and Gordon, 2007 with permission). Murine

thioglycollate elicited peritoneal macrophages were cultured in

the presence or absence of IL-4 on Permanoxs plastic for 24 h.

Two set of macrophages were labeled with CFSE (green) and

PKH26 (red), respectively, to facilitate quantification of

fusion. After IL-4 treatment, bi-fluorescent giant cells were

identified.

also favours Leishmania infection by inhibiting MCP-1stimulated killing of Leishmania major by humanmacrophages (Ritter and Moll, 2000).

During parasitic infection, the Th-2-type response,especially IL-4, seems to play a role in the formation ofmultinucleated giant cells (Fig. 4). Kao et al. (1995)described that IL-4 also contributes to the formation ofgiant cells in the response to foreign bodies. IL-4 inducesgiant cell formation via macrophage fusion (McInnesand Rennick, 1988), which depends on the STAT-6pathway and may involve an essential adhesion step viaE-cadherin. DC-STAMP has also been implicated in thefusion mechanism (Helming and Gordon, 2007; Morenoet al., 2007; Yagi et al., 2007). However, whether giantcell formation is a protective host response or whether itis induced by the foreign body to evade the immunesystem remains unclear.

Effect of alternative activation on macrophage

membrane functions

Alternative activation of macrophages also leads toaltered receptor expression pattern associated withmodification of phagocytosis and membrane trafficking(Table 3). One characteristic of AAMF is the increase inmannose receptor (MR) expression (Doyle et al., 1994;Stein et al., 1992). The MR is an important route foruptake of a broad range of mannosylated glycoproteinsand particulates (Stahl et al., 1980). Besides the MR,AAMF preferentially express other pattern recognitionreceptors of innate immunity, with a broad specificityfor foreign antigen, such as the b glucan receptor, inparticular Dectin 1 (Willment et al., 2003). Other studieshave shown that IL-4 increases the expression ofmacrophage galactose-type C-type lectins which mediateuptake of galactosylated glycoproteins and act asrecognition molecules for glycosylated antigens andcancer cells (Ichii et al., 2000; Kawakami et al., 1994).Moreover, increased expression of these lectins couldplay a role in the effector functions and in homing ofAAMF and modulate the activation state of themacrophage and its immune environment. Increasedexpression of these receptors favors uptake of differentpathogens and is associated with enhanced expression ofMHC-II molecules such as HLA-DR and HLA-DQ,associated with increased antigen presentation (de WaalMalefyt et al., 1993) as well as inducing differentiationof naıve T cells into antigen-specific Th-2 cells (Cua andStohlman, 1997).

An interesting but poorly understood effect ofalternative activation is the modification of membranetrafficking, endocytosis and phagocytosis. A strikingexample is the process of autophagy, a fundamentalhomeostatic mechanism in which cells sequester discrete

ARTICLE IN PRESS

Table 3. Modification of endocytic and phagocytic pathways in IL-4 activated macrophages.

Effect on endocytic and phagocytic pathway References

Activation of pinosome formation and membrane turnover Cipriano et al. (2003), Montaner et al. (1999), Stahl et al.

(1980) and Wainszelbaum et al. (2006)

Induction of MR and non MR-mediated uptake

Increased fluid phase uptake Chapuis et al. (1997), Pickl et al. (1996), Sallusto et al. (1995),

Sallusto et al. (1996) and Wainszelbaum et al. (2006)

Decreased Fc-dependent uptake Becker and Daniel (1990) and Cipriano et al. (2003)

Induction of ER and Golgi apparatus Cipriano et al. (2003)

Induction of early endosome maturation Montaner et al. (1999) and Wainszelbaum et al. (2006)

Modulation of cytoskeleton Araki et al. (1996) and Jay et al. (2007)

Regulation of macro- and micropinocytosis Araki et al. (1996), Racoosin and Swanson (1989), Raveh et al.

(1998) and Swanson et al. (1985)

Inhibition of IFNg induced phagosome maturation Harris et al. (2007)

Activation of pinosome formation and membrane turnover Cipriano et al. (2003), Montaner et al. (1999), Stahl et al.

(1980) and Wainszelbaum et al. (2006)

Induction of MR and non MR-mediated uptake

Fig. 5. IL-4 increases tubular vesicle formation at the

pericentriolar region, associated with trafficking of recycling

and early endosomes in human macrophages (Montaner et al.,

1999, with permission). The electron micrograph shows

endosomal morphology under the plasma membrane and in

perinuclear areas from human IL-4-treated macrophages. Cells

were treated with IL-4 for 72 h and pulsed with HRP before

ultrastructural analysis. A (untreated) and C (IL-4 treated)

show the area underneath the plasma membrane; B (untreated)

and D (IL-4 treated) show the perinuclear area. A bar graph

representing 1mm is indicated in D.

A. Varin, S. Gordon / Immunobiology 214 (2009) 630–641636

portions of cytoplasm into autophagosomes which inturn deliver them to lysosomes for degradation (Levine,2005; Shintani and Klionsky, 2004). Autophagyhas been shown to be involved in innate immunityagainst intracellular pathogens such as Mycobacterium

tuberculosis (Gutierrez et al., 2004). Harris et al. haverecently shown that IL-4 inhibited autophagosomeformation induced by starvation and reduced thenumber of IFNg-induced autophagic vacuoles. Thestudy also showed that during mycobacterial infection,alternative activation of macrophages did not affectphagosome maturation, but inhibited autophagy-depen-dent maturation and killing of mycobacteria (Harriset al., 2007). These data provide evidence for a novelrole for Th-1/Th-2 polarization, to modulate autophagyas an important immune effector mechanism. Inaddition, these data confirm the inability of alternativeactivation of macrophages to protect the organismagainst selected intracellular pathogens by modulatingintracellular membrane trafficking.

Alternative activation of macrophages by IL-4 hasbeen shown to enhance fluid-phase pinocytosis andMR-mediated endocytosis through activation of PI3K.IL-4 increased tubular vesicle formation at the pericen-triolar region, associated with trafficking of recyclingand early endosomes, concurrent with decreased particlesorting to lysosomes (Fig. 5). The endosomal stimula-tion by IL-4 may support increased antigen uptake andpresentation of soluble extracellular antigens, providinga mechanism for T cell-dependent enhancement ofantigen uptake by bystander macrophages (Montaneret al., 1999). In long term cultures, monocytes treatedwith IL-4/GMCSF develop a dendritic cell-like pheno-type with high rates of fluid phase and MR-mediateduptake and increased antigen presentation (Chapuiset al., 1997; Cipriano et al., 2003; Raveh et al., 1998;Sallusto et al., 1995). These results were confirmed by

Wainszelbaum et al. (2006) who showed thatPGE2+IL-4 increased early endosome size associatedwith an increase of MR-mediated and fluid-phaseendocytosis by M-CSF bone marrow-derived macro-phages. Curiously, in this study, IL-4 alone did notinduce formation of enlarged early endosomes.

ARTICLE IN PRESSA. Varin, S. Gordon / Immunobiology 214 (2009) 630–641 637

AAMF also display modifications of other compo-nents of the endocytic pathway. Cipriano et al. (2003)demonstrated that IL-4 induced an increased size of theendoplasmic reticulum and Golgi compartments ofperitoneal macrophages. AAMF can acquire the phe-notype of epithelioid cells associated with foreign bodygranulomatous lesions. Moreover, alternative activationof macrophages is associated with modulation of thecytoskeleton. Lamellipodia formation, a key feature ofthe IL-4-modified cytoskeleton in macrophages, isthought to occur via Rac-1 activation. However,inhibition of IL-4-induced lamellipodia formation didnot modify the uptake of latex beads (Jay et al., 2007).IL-4 also induced a relative increase in MR-independentuptake (micro- and macropinocytosis) associated withthe activation of PI3K and actin polymerization (Arakiet al., 1996).

Taken together these data show that AAMF act atthe site of inflammation by modifying endocytosisand phagocytosis of pathogens to protect the host.However, different papers show conflicting results onthe uptake of microorganisms. For example, Gratchevet al. (2005) demonstrated that IL-4 stimulates phago-cytosis of both opsonised and non-opsonised E. coli

compared with IFNg. However, the uptake of opsonisedor unopsonised E. coli is the same in IL-4-treated anduntreated macrophages, whereas Raveh et al. (1998)showed an increase of the phagocytosis of Saccharo-

myces cerevisiae by thioglycollate elicited peritonealmacrophages after IL-4 treatment. Likewise, IL-4stimulation of murine macrophages increased phagocy-tosis and killing of the parasite Trypanosoma cruzi

(Wirth et al., 1989), but did not modify trophozoiteuptake (Belosevic and Daniels, 1992). A recent paperindicated that the IL-4/STAT6 pathway limited thephagocytosis of small particles by the macrophages(Moreno et al., 2007). Overall these different resultsindicate that the nature of cellular changes andfunctions of AAMF are complex and are yet to be fullycharacterized.

Conclusion

AAMF seem to be major players in the immunesystem by preventing excessive inflammation whiledown-regulating host protection against differentpathogens. These effects are linked to the modulationof expression of receptors at the cell surface andby modification of the endocytic and phagocyticpathway. A possible link to altered secretory activityand extracellular functions remains to be established.Moreover, AAMF are characterized by increaseof scavenging and membrane trafficking associatedwith tissue remodeling, healing, and control of theinflammation.

Acknowledgments

Audrey Varin is supported by a fellowship fromFondation pour la Recherche Medicale. Work in thelaboratory of Siamon Gordon is supported by grantsfrom the Medical Research Council, UK. We thankLaura Helming and Fernando Martinez for the criticalreading of this manuscript.

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