A critical review of the roles of host lactoferrin in immunity

A critical review of the roles of host lactoferrin in immunity

Dominique Legrand ?Joe

¨l Mazurier Received:22December 2009/Accepted:25January 2010/Published online:9February 2010

óSpringer Science+Business Media,LLC.2010

Abstract Lactoferrin (Lf)is an essential element of innate immunity,which refers to antigen-nonspeci?c defense mechanisms that a host uses immediately or within hours after exposure to an antigen.Following infection,Lf is released from neutrophils (PMNs)in blood and in?amed tissues and,such as other soluble pattern-recognition receptors of the innate immunity,Lf recognizes unique microbial molecules called pathogen-associated molecular patterns (PAMPs):LPS from the gram-negative cell wall and bacterial unmethylated CpG DNA.However,unlike classical PAMPs receptors involved in the activation of immune cells,Lf may act either as a competitor for these receptors or as a partner molecule,depending on the physiological status of the organism.These immunomodulatory properties are explained by the ability of Lf to interact with proteoglycans and receptors on the surface of mammalian cells:cells of the innate (NK cells,neutrophils,macrophages,basophils,neutrophils and mast cells)and adaptive [lymphocytes and antigen-presenting cells (APCs)]immune systems,and also epithelial and endothelial cells.Through these interactions,Lf is able to modulate the migration,maturation and functions of

immune cells,and thus to in?uence both adaptive and innate immunities.The understanding of the roles of the host-expressed Lf in immunity comes from in vivo and in vitro studies with exogenous Lf which,although informative,rarely re?ect the pathological,or non-pathological,conditions in the organism.In this review,the data from the literature will be critically analyzed in order to present a real picture of the regulatory roles of host Lf in immunity.Keywords Lactoferrin áImmunity áImmunomodulation áImmune cells áLipopolysaccharides

Introduction

Depending on the organism,immunity may involve innate immunity only,as for most invertebrates,or both innate and adaptive immunities,as for mam-mals.Whatever the systems brought into play,they are always complex and tightly regulated because they intend to be as harmful as possible against the infectious agents whereas they must be as harmless as possible for the host https://www.sodocs.net/doc/1d13181244.html,ctoferrin (Lf)is de?nitely one of the molecules that play key roles not only against microbes but also against excessive and harmful host responses in mammals:a sword and a shield at the same time.Those two aspects of Lf roles in host defense,together with its potency to modulate both innate and adaptive immunities,make

D.Legrand (&)áJ.Mazurier

Structural and Functional Glycobiology Unit,UMR 8576

CNRS-USTL,IFR 147,Ba

?timent C9,Universite ′des Sciences et Technologies de Lille,59655Villeneuve d’Ascq cedex,France

e-mail:dominique.legrand@univ-lille1.fr

Biometals (2010)23:365–376DOI 10.1007/s10534-010-9297-1

Lf an amazing multifunctional molecule in immunity. Until now,a plethora of studies aimed to demonstrate activities of Lf in immunity(reviewed in Legrand et al.2004a,2005,2008);we will try to depict here the actual roles of host-expressed Lf in the immune responses.

Evidences for roles of Lf in immunity:in vivo and in vitro experiments

In vivo evidences

The multifunctionality of Lf makes the understanding of its activities very tricky(reviewed in Legrand et al. 2008).The literature is indeed crammed of evidences for roles of Lf in the host defense but,unfortunately, most of them are not necessarily informative on the actual mechanisms of action of the host molecule in immunity.Indeed,whereas many in vivo studies reported protective effects against infections or septic shock(reviewed in Legrand et al.2005,2006),it is not perfectly clear whether those effects are the result of a direct anti-microbial activity or of a boost of cell-mediated immunity modulation.However,recent studies undoubtly demonstrate that bovine Lf(bLf) supports immune and antioxidant status in healthy human volunteers(Mulder et al.2008).In addition to the evidence that Lf levels markedly increased in biological?uids of patients suffering of in?ammatory diseases(Bennett and Kokocinski1978),the main in vivo indications of the role of Lf in the host defense came from observations on organisms suffering a lack of Lf synthesis.In particular,Breton-Gorius et al. (1980)showed a lack of speci?c granules in neutro-phils from a patient with recurrent infections and, recently Ward et al.(2008),demonstrated a stimulus-dependent impairment of the neutrophil oxidative burst response in Lf-de?cient mice.Conversely, Guillen et al.(2002)showed that transgenic mice expressing human Lf(hLf)exhibit enhanced Th1 response to S.aureus.However,although very demonstrative,this study and almost all others were performed with Lf from exogenous sources,usually coming from species different from that of the animal model used in the experiments,usually administered by oral route but also by intraveinous injection,and generally in large amounts.All these parameters are likely to generate effects that greatly differ from those of the host protein in physiological conditions,but which do re?ect the immunomodulatory potency of Lf. In vitro evidences

In vitro approaches are very suited to comprehend the actual roles of Lf in immunity,provided that the studies are conducted in homologous conditions(e.g., hLf with human cells)and with reagents of the highest purity and quality.As we will see thereafter, Lf binds the lipopolysaccharides(LPS)with high af?nity(Appelmelk et al.1994;Elass-Rochard et al. 1995)and these pro-in?ammatory components are common contaminants in Lf preparations which can readily activate transduction pathways of the in?am-matory response(usually MAP kinase and NF j B pathways;reviewed in Guha and Mackman(2001)). Furthermore,Lf protease degradation may generate peptides with different and/or higher activities than the whole protein[e.g.,lactoferricin(Lfc),the N-terminal domain of Lf(Gifford et al.2005)].All the in vitro studies have demonstrated a role of Lf in the modulation of the activation of the cells involved either in innate immunity(most particularly macro-phages,neutrophils,basophils,esosinophils,masto-cytes and NK Cells)or in adaptive immunity(B and T-cells and dendritic cells),either as a pro-in?am-matory or an anti-in?ammatory agent(reviewed in Legrand et al.2005,2006).In most cases,the modulation of the activity of immune cells by Lf results in decreased or increased expressions of pro-in?ammatory interleukins(IL-1,IL-6,IL-18,TNF-a) by immune cells or adhesion molecules by endothe-lial cells(E-selectin;Elass et al.2002).Whereas most of the anti-in?ammatory properties of Lf may be explained by a neutralizing effect of Lf against endotoxins,especially LPS,and their related recep-tors(see thereafter;reviewed in Legrand et al.2005, 2006),the pro-in?ammatory effects are much more controversial.Owing to the putative presence of LPS in Lf preparations used in some experiments,it is likely that the LPS itself may be the causative agent of pro-in?ammatory effects.However,as discussed thereafter,it may be hypothesized that,in some instances,Lf may serve as a carrier for LPS.In addition to endotoxin binding,interactions of Lf with membrane components on cells,such as proteogly-cans and cell receptors(reviewed in Suzuki et al. 2005;Legrand et al.2008),were reported through in

vitro experiments which support a direct action of Lf on the activity of immune cells,most particularly on the proliferation,maturation and differentiation of lymphocytes(Mazurier et al.1989;Bi et al.1997). Occurrence of host Lf in immunity:where,when and how?

The wide-spread distribution of the molecule in the organism testi?es that Lf is in the front line of the host defense system.Lf is secreted in the apo-form from epithelial cells in most exocrine?uids such as saliva, bile,pancreatic and gastric?uids,tears and,more particularly milk(Montreuil et al.1960).In biological ?uids and at the surface of mucosa,Lf is believed to exert its antibacterial activities,either by direct inter-actions with microbes or by competition with bacterial siderophores(Jenssen and Hancock2009).It repre-sents,like other antibacterial proteins and peptides in ?uids,an important key molecule of innate immunity.

When a microbe penetrates the tissues,itself and released endotoxins will activate the so-called‘‘sen-tinel cells’’,such as macrophages,basophils,eosin-ophils,?broblasts and dendritic cells,which will release very potent pro-in?ammatory molecules (particularly IL-1,IL-6and TNF-a).Both compo-nents and endotoxins will then activate the endothe-lial cells of which the permeability properties will be greatly modi?ed.Endothelial cells will thus allow not only the passage of soluble molecules such as the complement and antibodies,but also the recruitment of blood-circulating neutrophils.This important step is made possible by the expression of speci?c adhesion receptors on activated endothelial cells(P-and E-selectins)and chemiokines(Il-8).Obviously, the recruitment of neutrophils by activated endothe-lial cells will initiate their activation and,as a result,a partial release of the content of their secondary granules in blood.Since Lf is a major component of secondary granules,its concentration in plasma may greatly increase from0.4to2mg l-1to up 200mg l-1(Bennett and Kokocinski1978).Plasma Lf is then rapidly cleared by the liver parenchymal cells(Debanne et al.1985).In fact,plasma Lf only represents the tip of the iceberg since most of neutrophil Lf is delivered by neutrophils at very high concentration at the sites of in?ammation where maximal activation of cells occurs.Degranulated Lf is in the form of the apo protein,so that its iron-chelating properties can be directed against microbes together with the direct microbicidal activity of the molecule.Besides its antimicrobial role,an important function of Lf is the modulation of the activity of the sentinel cells,either in pro-or anti-in?ammatory ways(reviewed in Legrand et al.2005,2006).

These regulating activities take place thanks to the iron-binding properties of Lf and above all to its ability to interact with target molecules and cells.On one side,some in vitro experiments suggest that it may regulate proliferation,differentiation and acti-vation of immune cells,thus strengthening,either directly or indirectly,the immune responses.On the other side,Lf plays anti-in?ammatory activities able to lower harmfulness of the response.When tissues are infected,reactive oxygen species are abundantly produced,either generated by free iron released from necrosed tissues or overproduced by actived granu-locytes.That oxydative burst,together with the excessive release of pro-in?ammatory cytokines, mainly interleukin-1(IL-1)and tumor necrosis factor (TNF-a)highly contributes to the pathogenesis of the septic shock(Annane et al.2005).The protective anti-in?ammatory activity of Lf lies in its ability to bind free ferric ion but also exogenous pro-in?am-matory bacterial components such as lipopolysaccha-rides(LPS)and their receptors.Whereas Lf iron binding has bene?cial detoxication effects in infected or pathological tissues,binding to pro-in?ammatory molecules has down-regulating effects on both the activation and recruitment of immune cells in in?amed tissues(reviewed in Legrand et al.2005, 2006).Molecular and cellular basis supporting these assertions are developed in the following sections. Lf modulates the activation of immune

cells by microbial components

Lf binds to major pathogen-associated molecular patterns

Pathogens,especially bacteria,have common and relatively invariant molecular structures that are not shared with their host,known as Pathogen-Associated Molecular Patterns(PAMPs;reviewed in Akira and Hemmi2003),which are powerful activation signals. The main PAMPs are the?agellin of bacterial

?agella,the peptidoglycan of Gram-positive bacteria, the lipopolysaccharide(LPS,also called endotoxin) of Gram-negative bacteria,double-stranded RNA (viruses)and unmethylated DNA.These molecules are recognized by the Pattern-Recognition Receptors (PPRs)which are the key elements of innate immu-nity,of which three main groups exist:the secreted PPRs(e.g.,the C-reactive protein),the phagocytosis receptors(e.g.,the mannose receptor),and the Toll-Like Receptors(TLRs).

Interestingly,it was reported that Lf binds to two major PAMPs:the LPS and unmethylated CpG DNA (Appelmelk et al.1994;Elass-Rochard et al.1995, 1998;Britigan et al.2001).In the case of LPS,high-af?nity interaction of Lf with the lipid A moiety of E. coli LPS was reported(Appelmelk et al.1994).Using E.coli LPS,two binding sites with dissociation constants(Kds)of 3.6±1nM and390±20nM were found on the N-and C-lobes of hLf(Elass-Rochard et al.1995).It was shown that both sequences 1GRRRR5and28RKVRGPP34,the same involved separately or in conjunction in the interactions with the 105kDa Lf receptor,the LRP,glycosaminoglycans and DNA(Mann et al.1994;Legrand et al.1997;van Berkel et al.1997)are required for the high-af?nity binding of Lf to LPS(Elass-Rochard et al.1995).

Although Lf could not be strictly considered as a PPR because it does not directly induce cell activa-tion following binding to LPS or unmethylated CpG DNA,it may act as a competitor for the PPRs,or even,in some instances,as a transfer molecule.

Lf inhibits LPS signaling

A PPR such as the TLR4,the LPS signaling PPR,uses a serum transfer molecule called the LPS-binding pro-tein(LBP),which transfers LPS to CD14.CD14can either be soluble in serum or GPI-anchored to the cell membrane of neutrophils,monocytes/macrophages and lymphocytes(reviewed in Jerala(2007)).Soluble CD14(sCD14)in complex with LPS binds to cells, such as endothelial cells,which do not express mCD14.

As shown through in vivo and in vitro experi-ments,hLf suppresses TNF-a,IL-1b,IL-6produc-tions in mononuclear cells in response to LPS activation(Miyazawa et al.1991;Crouch et al. 1992;Mattsby-Baltzer et al.1996;Haversen et al. 2002;Kruzel et al.2002).In particular,orally-administered bLf was shown to have a bene?cial effect on infections and protects animals against a lethal dose of LPS(Zagulski et al.1989).It is now well admitted that the down-regulation of pro-in?ammatory cytokines and protection against the septic shock is mainly related to the LPS-binding properties of Lf,through its lactoferricin(Lfc) domain(Elass-Rochard et al.1995,1998).Lf com-petes with serum LBP for LPS binding and therefore prevents the transfer of endotoxin to mCD14pre-sented at the surface of neutrophils(Elass-Rochard et al.1998).This property accounts for the inhibition by Lf of LPS-induced activation and subsequent release of proin?ammatory cytokines by immune cells.Another important?nding was the evidence of high-af?nity interactions(Kd&16±7nM)between Lf and sCD14(Baveye et al.2000a).It was showed that hLf interacts not only with free sCD14but also, though with different binding properties,with sCD14 in complex with LPS or lipid A-2-keto-3-deoxyoc-tonic acid-heptose.As for LPS,the cationic N-terminal peptides of Lf are essential in the binding (Baveye et al.2000a).Lf also suppresses the production of hydrogen peroxide mediated by the binding of LPS to L-selectin of neutrophils(Baveye et al.2000b).Furthermore,the interaction between Lf and soluble CD14(sCD14)inhibits the secretion of IL-8,a chemokine induced by the complex sCD14-LPS,by endothelial cells(Elass et al.2002).The interaction of Lf with LPS and sCD14interferes not only with the activation of immune cells but also with the expression of adhesion molecules on endothelial cells,necessary for the local recruitment of immune cells at in?ammatory sites.In particular,Lf inhibits the(sCD14-LPS)-induced expression of E-selectin, ICAM-1and IL-8by human umbilical endothelial cells(Baveye et al.2000a;Elass et al.2002).

In conclusion,it is very likely that when Lf is released in high amounts at the in?ammatory sites and in lesser extent in blood,it may prevent further binding of LPS to the receptors,thus preventing the activation of cells and playing a potent anti-in?am-matory role in immunity.

Lf,a vector for LPS?

Several studies have reported that Lf may activate macrophages and induce IL-8,TNF-a and NO (Sorimachi et al.1997).During infection,Lf secreted from neutrophil granules can bind to PMNs and

monocytes/macrophages(Gahr et al.1991),and a connection was made between this binding and the promotion of the secretion of in?ammatory molecules such as TNF-a(Sorimachi et al.1997).Studies have shown that Lf may activate macrophages via TLR4-dependent and independent signalling pathways (Curran et al.2006).This activation induces CD40 expression and IL-6secretion.However,it is not clear whether Lf activates cells on its own,or if the observed effect is due to contaminating LPS in Lf preparations.Since(1)only traces of LPS are suf?cient to trigger activation of cells,and(2) signi?cant amounts of LPS were detected in com-mercial preparations of Lf,it is possible that many studies actually reported the effect of LPS or the Lf-LPS complex on immune cells.

Indeed,in some conditions,the Lf-LPS complex could be an inducer of in?ammatory mediators in macrophages,through Toll-like receptor4(Na et al. 2004).Moreover,after a pre-treatment with the Lf-LPS complex,it was found that cells are rendering a tolerant state to LPS challenge(Na et al.2004).It was also recently demonstrated that a complex of Lf with monophosphoryl lipid A is an ef?cient adjuvant of the immune responses(Chodaczek et al.2006, 2008).Lastly,it was recently reported that the ability of Lf to form complexes with LPS would induce IFN-a/b expression and hence promote the antiviral activity of Lf(Puddu et al.2007).

We thus hypothesize that depending on the Lf/LPS ratio at a particular site of in?ammation or in a particular biological?uid,and depending on the nature and maturation of immune cells,Lf may act either as a LPS neutralizing molecule or as a LPS carrier,hence its immunomodulatory activity.In other words,when the Lf/LPS ratio is elevated,as when Lf is released from PMNs at the sites of in?ammation,Lf could act as a LPS neutralizing and anti-in?ammatory molecule.However,when Lf con-centration is lower,Lf could serve as a carrier for LPS whose delivery would depend on the cell environment.It is indeed worth noting that most interactions of Lf with its receptors and ligands, including LPS,involve the basic Lfc domain of the molecule.Cell surface and extracellular matrix proteoglycans are precisely major targets of the Lfc domain(Mann et al.1994;Ziere et al.1996;Legrand et al.1997).On most cells,in particular on T-lymphocytes,binding to proteoglycans accounts for more than80%of total Lf binding on cell surface (Legrand et al.1997).It is thus very likely that the Lf/ LPS complex readily dissociates at the vicinity of the extracellular matrix(ECM)or in contact with the surface of cells.It is a fact that the af?nity of Lf for LPS is about500-fold lower than that for proteogly-cans but the tremendous number of Lf-binding sites on cell proteoglycans(usually several millions sites per cell),and most particularly on ECM proteogly-cans,largely compensates this difference.Interest-ingly,both nature and number of proteoglycans greatly depend on the nature of cells but also on their state of differentiation or maturation,but also of pathologies(Schwartz2000).It is thus quite con-ceivable that dissociation of the Lf/LPS complex occurs more readily on certain cells than on others. After dissociation from proteoglycan-bound Lf,LPS would bind to any LPS receptor present on the cells, thus initiating the activation of cells.

Lf modulates the recruitment of immune cells

Cell migration is critical for a variety of biological processes.During in?uenza virus infection(pneumo-nia),bLf was shown to reduce the number of in?ltrat-ing leukocytes in bronchoalveolar lavage?uid,thus suppressing the hyper reaction of the host(Yamauchi et al.2006).Lf also decreases the recruitment of eosinophils,reduces pollen antigen-induced allergic airway in?ammation in a murine model of asthma (Kruzel et al.2006),and reduces migration of Langh-erans cells in cutaneous in?ammation(Grif?ths et al. 2001).Such reduced migration of granulocytes,most particularly eosinophils,was recently reported(Bour-nazou et al.2009).Furthermore,Lf can modulate ?broblast motility by regulating MMP-1gene expres-sion,a matrix metalloproteinase involved in the promotion of cell migration(Oh et al.2001).Lastly, an in vivo study has shown that orally-administered recombinant hLf is able to prevent injury of non-steroidal anti-in?ammatory drugs in the intestine of rats and mice and that this effect could be linked to attenuation of neutrophil migration to the intestine (Dial et al.2005).Another aspect of Lf activity could be the inhibition of angiogenesis,probably by inducing IL-18production in serum and blocking endothelial functions(Shimamura et al.2004).

Although the exact mechanism of action of Lf in these processes was not clearly de?ned,it has been

demonstrated in vitro that Lf inhibits the(sCD14-LPS)-induced expression of E-selectin,ICAM-1and IL-8by human umbilical endothelial cells(Baveye et al.2000a,b;Elass et al.2002).These studies also pointed out the ability of Lf to compete with chemokines such as IL-8for their binding to prote-oglycans and their further presentation to leukocytes (discussed after).Other mechanisms of action of Lf in allergy were proposed.Indeed,Lf is over expressed in patients with allergies(Zweiman et al.1990),a process which involves the activation of mast cells and basophils and IL-1b and TNF-a-triggered migra-tion of APCs.In skin allergies,a mechanism by which Lf binds to keratinocytes and inhibits the release of TNF-a from these cells has been proposed (Cumberbatch et al.2003).Another explanation has been found in the ability of Lf to displace tryptase(a potent pro-in?ammatory protease released from mast cells)from heparin,and hence to destabilize the enzyme(Kimber et al.2002).Lf apparently displaces tryptase from heparin which is known to maintain enzymatic activity.It was recently shown that inhibition occurs following Lf uptake by mast cells and interaction not only with tryptase but also with chymase and cathepsin G(He et al.2003).These authors also showed an inhibition of anti-IgE induced histamine and tryptase releases from human colon mast cells by Lf(Elrod et al.1997;He and Xie2004). The role of proteoglycans in the activity of Lf

in immunity

Glycosaminoglycans and proteoglycans participate in a variety of biological processes including the in?ammatory process(Taylor and Gallo2006).Since Lf is a glycosaminoglycan-binding protein(Mann et al.1994;Ziere et al.1996;Legrand et al.1997),it may be expected that massive Lf release from PMNs at the in?ammatory sites and in blood interferes in proteoglycans functions.

Interleukin-8(IL-8),a potent C-X-C chemokine activates LFA-1integrins(LFA-1)on neutrophils but also binds,as a dimer and with a low af?nity,to heparin and heparan sulfate molecules(reviewed in Mukaida2000).Once?rmly attached,the cells are directed by a chemo attractant gradient to transmi-grate into tissue affected by injury or infection(Smith et al.1991).The cell surface proteoglycans increase the local concentration of IL-8that,in turn,regulates the activation of neutrophils through speci?c inter-actions with a G-protein coupled receptor.We showed in vitro that Lf inhibits the interaction of IL-8to immobilized heparin,thus suggesting that the anti-in?ammatory properties of Lf during septicemia is related,at least in part,to the ability of Lf to compete with chemokines for their binding to prote-oglycans on cells and in the ECM(Elass et al.2002).

Another role of Lf binding to glycosaminoglycans, still hypothetical though and above outlined,is the destabilization of the Lf-LPS complex,making LPS available to its signaling cell receptors.

Lf modulates the phagocyte capacity of cells Promotion of lytic cell activity is an important aspect of Lf function.Lf is already expressed on resting PMNs where it could participate in the binding of micro-organisms(Deriy et al.2000).It was shown in vitro that both release and cell binding promote the activation and phagocytosis of PMNs and monocytes/ macrophages.Lf was reported as a promoter of motility,superoxide production and release of pro-in?ammatory molecules such as NO,TNF-a and IL-8 (Gahr et al.1991;Shinoda et al.1996;Sorimachi et al. 1997)and a study indeed demonstrates enhanced phagocytosis against S.aureus(Kai et al.2002).The molecular mechanisms explaining these activities are, however,controversial.Phagocytosis by PMNs is enhanced by the interaction of complement activation products,particularly complement factor C3.Never-theless,it is unclear whether Lf activity is related to complement activation since Lf was shown either to inhibit(Kijlstra and Jeurissen1982)or to activate (Rainard1993)the classical and alternate pathways of complement.A more recent report shows that the Lfc domain of either hLf or bLf inhibits the classical complement pathway but not the alternative comple-ment pathway(Samuelsen et al.2004).Lastly,direct Lf binding to PMNs and opsonin-like activity could also be involved(Miyauchi et al.1998).

Host Lf,a bridge between innate and adaptive immunities?

Whereas there is no doubt that Lf plays a key role in innate immunity,many studies have shown that Lf also intervenes in adaptive immunity.In particular,

oral administration of bLf seems to in?uence mucosal and systemic immune responses in mice(Sfeir et al. 2004).These effects may be explained by roles of Lf in the modulation of the maturation,differentiation and activity of lymphocytes,and in the promotion of antigen presentation to these cells.

Modulation of the maturation,differentiation

and activity of lymphocytes by Lf

Many studies reported effects of Lf on the maturation and differentiation of T-and B-lymphocytes. Although most results were obtained from in vivo studies using oral administration of Lf,it may be assumed that increased concentrations of Lf in blood and biological?uids during in?ammation(Bennett and Kokocinski1978)would also in?uence the maturation and differentiation of lymphocytes.It was demonstrated that bLf administered orally to mice strongly elevated the pool of CD3?T cells and CD4?T cell content(Sfeir et al.2004).Lf given orally to CP-immunosuppressed mice could reconsti-tute a T cell-mediated immune response by renewal of the T cell pool(Artym et al.2003b).It was also recently demonstrated that a complex of Lf with monophoshoryl lipid A is an ef?cient adjuvant of the humoral and cellular immune responses(Chodaczek et al.2006).Its stimulating effect on the immune system mainly concerns the maturation and differen-tiation of T-lymphocytes and the Th1/Th2cytokine balance(Fischer et al.2006).Under non-pathogenic conditions,Lf is able to stimulate the differentiation of T cells from their immature precursors through the induction of CD4antigen(Zimecki et al.1991; Dhennin-Duthille et al.2000).A similar effect was described on isolated thymocytes incubated overnight with Lf.Furthermore,oral delivery of Lf signi?cantly increased the number of CD4-positive cells in lymphoid tissus(Kuhara et al.2000).Lf induces a Th1polarization in diseases in which the ability to control infection or tumor relies on a strong response, but may also reduce Th1cytokines to limit excessive in?ammatory responses.Thus,Lf enhances both the ability of Th cells to assist the fungicidal actions of macrophages(Wakabayashi et al.2003)and BCG vaccine effectiveness against challenge with Myco-bacterium tuberculosis(Hwang et al.2005,2008). Similarly in Lf transgenic mice,an upregulation of the Th1response was associated with S.aureus clearance(Guillen et al.2002).Oral administration of Lf increased the splenocyte production of IFN-c and Il-12in response to Herpes simplex virus type1 infection(Wakabayashi et al.2004).An up-regula-tion of IFN-c and TNF-a production by cervical lymph node cells stimulated by heat-killed Candida albicans was observed in Lf-treated mice compared with non-treated mice(Takakura et al.2004).Lastly, the eradication of chronic hepatitis C virus by IFN therapy is favourized by administration of bLf that induces a Th-1cytokine dominant environment in peripheral blood(Ishii et al.2003).

Concerning the humoral response,Lf was shown, in vitro,to promote differentiation of splenic B cells (Zimecki et al.1995).Lf also restored humoral immune response by peritoneal and alveolar cells in cyclophosphamide(CP)-immunocompromised mice (Artym et al.2003a,2004).Lastly,Lf binding to CpG-containing oligonucleotides was shown to inhibit their immunostimulatory effects on human B cells(Britigan et al.2001).

Lf promotes the recruitment,maturation

and activation of antigen-presenting cells

A connection between innate and adaptive immuni-ties made by host-expressed Lf can be found at the very place where Lf is degranulated in large amounts from neutrophils,i.e.,the in?ammatory site.As described above,APCs,among which dendritic cells, the most important T helper cell activators,are present in all tissues.Recently,it has been shown that Lf acts as an alarmin to promote the recruitment and activation of APCs and antigen-speci?c immune responses(de la Rosa et al.2008).It was also reported as a novel maturation factor for dendritic cells(Spadaro et al.2008).Hence,Lf released at the in?ammatory site would participate to adaptive immunity by promoting the maturation,activation and migration of APCs(reviewed in Puddu et al. 2009).

Putative mechanisms accounting for the effects

of Lf in adaptive immunity

The exact mechanisms by which Lf modulates the maturation,differentiation,migration and activation of lymphocytes and APCs are not clearly known.As

mentioned before,most results are obtained from studies using oral-administered Lf whose action is mainly directed in the intestine.A proposed mech-anism is that oral Lf induces IL-18production in the small intestine,therefore leading to an increase in the level of Th1cells(Ishii et al.2003).Furthermore,it has been shown that bLf may promote systemic host immunity by activating the transcription in the small intestine of important genes such as IL-12p40,IFN-b and NOD2(Yamauchi et al.2006).

Two main hypothetical mechanisms may account for effects of Lf on lymphocytes and APCs.The?rst mechanism,formerly mentioned in this review,relies on the ability of Lf to complex PAMPs and to serve either as a PAMP-neutralizing molecule or as a PAMP vector.Indeed,LPS have profound effects on CD4T-cell responses and are well-known for gen-erating Th1responses(McAleer and Vella2008). They also upregulate costimulatory molecules on antigen-presenting cells(APCs).T cells that are primed in an LPS-stimulated environment are pro-grammed for long-term survival following clonal expansion(McAleer and Vella2008).Hence,it may be hypothesized that the LPS-binding ability of Lf plays a modulatory role in the physiology and functions of lymphocytes,in a similar way to cells of innate immunity.The second mechanism is based on interactions of Lf with receptors at the surface of cells which would be responsible for the activation of signalling pathways and/or the endocytosis and targeting of all or part of Lf in the nucleus of cells. Whereas three protein receptors have been identi?ed on human cells,i.e.,the lipoprotein-related receptor (LRP;Meilinger et al.1995),the105kDa lympho-cyte receptor identi?ed as surface nucleolin(Legrand et al.2004b),and a speci?c receptor evidenced on intestinal cells(reviewed in Suzuki et al.2005),very little is known about the actual mechanisms of action of Lf on cells expressing these receptors.Interest-ingly,all three receptors permit signaling in cells and/ or endocytosis of Lf.LRP,a Lf receptor at the surface of many cells has been recently shown to function as a mitogenic Lf receptor in osteoblastic cells,via p42/ 44MAP kinase signaling(Grey et al.2004).Such MAP kinase signaling was also observed in Jurkat lymphoblastic T cells owing to the105kDa Lf receptor(Dhennin-Duthille et al.2000).It is also hypothesized that Lf may enter the cell and be targeted to the nucleus where it can act as a transcriptional activator(Oh et al.2001).Recently, nucleolin ubiquitously expressed on dividing cells was pointed out as a possible Lf carrier between cell surface and nucleus(Legrand et al.2004b).Interest-ingly,it was recently shown that Lf may down-regulate LPS-induced cytokines in THP1through a mechanism involving Lf internalization,nuclear localization and interference with nuclear factor-j B (NF-j B;Haversen et al.2002).The mechanisms of interference of Lf of NF-j B,a transcription factor playing a critical role in immune responses and in?ammation,are not perfectly clear.However,Oh et al.(2004)showed that overexpressed Lf acts as a p53gene transactivator through the stimulation of the I j B-kinase activity and NF-j B binding.These authors previously demonstrated a matrix metallo-proteinase1gene transactivating activity by Lf through stress-activated MAPK signaling modules (Oh et al.2001).

A role of host Lf in the maturation

and differentiation of lymphocytes?

As described above,most assertions of roles of Lf in adaptive immunity are based on either in vitro or in vivo experiments of which the physiological rele-vance may be questioned.Hence,the observations made in these experiments could poorly re?ect the exact role of host Lf in adaptive immunity.For example,about vaccine ef?ciency,an adjuvant effect in the generation of delayed-type hypersensivity and in the bost of BCG ef?cacy to generate T helper response in mice was demonstrated(Zimecki et al. 2002).However,this adjuvant effect was attributed to bLf binding on the mannose receptor of immature skin APCs.Such binding has been recently con?rmed in a study showing that bLf binding to DC-SIGN on dendritic cells blocks its interaction with HIV gp120 and subsequent virus transmission(Groot et al.2005). Since glycans with polymannosidic structures are speci?c to bLf and not found on hLf,this example clearly illustrates a typical‘‘non-speci?c’’effect of exogenous Lf in in vivo experiments.Most impor-tantly,since Lf is not synthesized/secreted in thymus or in any other primary or secondary lymphoid tissue, its presence in these tissues mostly originates from a transient release from degranulating neutrophils in blood.Therefore,unless in chronic and/or severe in?ammatory diseases,a possible effect of host Lf on

maturation and differentiation of lymphocytes should be questioned.

Conclusion

Lf possesses pleiotropic roles which turn it into either a weapon or a shield in the host defense system.The bene?cial effects of Lf administered in prevention or treatment of infectious pathologies have led to many applications for health.These applications have emphasized the importance of Lf in the regulation of immunity but most of them poorly account for the actual activities of host-expressed Lf in this control.It appears that Lf acts as an anti-microbial and anti-oxidant molecule,not only through direct interactions with microbes or through its iron-binding capability, but also by stimulating the migration and functions of cells of the innate and adaptive immunities(illus-trated in Fig.1).The immuno-modulatory properties of Lf are mainly related to its PAMPs(mostly LPS)-binding ability which generally turns Lf into an anti-in?ammatory molecule able to protect the host from harmful immune responses.Conversely,it may be hypothesized that Lf also acts as a vector of PAMPs for immune cell activation.Other putative mecha-nisms,which still need further investigations,would require signalling or nuclear targeting following interactions with multifunctional or speci?c cell membrane receptors.

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