Alternative Review Activation of Antigen-Presenting Cells

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Immunity, Vol. 10, 137–142, February, 1999, Copyright 1999 by Cell Press Other Functions, Other Genes: Alternative Review Activation of Antigen-Presenting Cells

Sergij Goerdt* and Constantin E. Orfanos activation pathway. On the contrary, anti-inflammatory Klinik und Poliklinik fu¨ r Dermatologie agents such as interleukin (IL)-4 and glucocorticoids Universita¨ tsklinikum Benjamin Franklin were shown to inhibit expression of proinflammatory Freie Universita¨ t Berlin cytokines by macrophages, and this finding was inter- Hindenburgdamm 30 preted as indicative of macrophage deactivation. More D-12200 Berlin recently, however, IL-4 and glucocorticoids were found Germany to induce increased expression of the macrophage mannose receptor and to enhance the capacity for endocy- tosis and antigen presentation of macrophages. Since ⌻␻␯ ⑀␯␣␯␶␫␻␯ ␩ ␸␷␴␫␵ ␥␭␫␹⑀␶␣␫ ␬␣␫ ⑀␬ ␶␱␷␶␻␯ ␣␲␱␶⑀␭⑀␫ this was proof against mere deactivation of macro- ␶␱ ␴␷␮φ␻␯␱␯. phages by anti-inflammatory agents, Gordon and col- Nature strives for the opposite and from it generates leagues instead introduced the concept of alternative consonance. immunologic activation of macrophages (Stein et al., 1992). Evidence has now accumulated which indicates —Herakleitos that alternatively activated macrophages express a special set of molecules enabling them to actively participate in anti-inflammatory processes, tolerance induc- In the course of inflammatory reactions, proinflamma- tion, and healing. Recently, dendritic cells known as tory mechanisms are most important to guarantee elimi- specialized antigen-presenting cells (APC) supporting nation of the causative infectious, toxic, or allergenic Th1 differentiation have also been shown to undergo agents. It is mandatory, however, that inflammatory pro- alternative activation under certain conditions. Here we cesses, once induced, do not escalate but are again revisit Gordon’s concept of alternative activation of APC downregulated to allow healing. Therefore, proinflam- and show that it fits well with what is known as “sup- matory and anti-inflammatory mechanisms must be acti- pressive” functions of APC (Figure 1). vated spatially and temporally in a finely tuned manner. The inflammatory processes in sepsis are a good exam- Molecular Repertoire of Alternatively ple for such a balanced interplay. Here, the causative Activated Macrophages agent is a microbial agent; however, massive secretion Alternative activation of macrophages may be induced of cytokines such as interleukin (IL)-1 or tumor necrosis by IL-4 and glucocorticoids as well as by other cytokines factor (TNF)-␣ actually mediates the detrimental devel- such as IL-10, IL-13, and transforming growth factor opments. Via neuroinflammatory interactions, the septic (TGF)-␤, with similar effects. Alternatively activated macro- organism tries to counteract the effects of these proin- phages express phenotypic and molecular characteris- flammatory cytokines; finally, glucocorticoids are syn- tics that differ considerably from those of classically thesized and secreted and may exert their pleiotropic activated macrophages. Regulation and expression of anti-inflammatory effects (Wilckens and De Rijk, 1997). inflammation-associated molecules and genes in mac- In addition, inflammatory diseases and allergies may not rophages is regulated antagonistically by IL-4 and IFN␥, only be due to an aberrant overwhelming proinflamma- i.e., alternative macrophage molecules are induced by tory reaction, but they can also be caused by dysfunc- IL-4 and inhibited by IFN␥, while classical macrophage tion or failure of anti-inflammatory control mechanisms. molecules are induced by IFN␥ and inhibited by IL-4 This notion was very recently confirmed by the finding (Table 1). Alternatively activated macrophages preferen- that certain mutations in a novel anti-inflammatory mole- tially express the receptors of innate immunity with cule of bronchial epithelium (CC16) are associated with broad specificity for foreign antigens such as the macro- a tremendous increase in the risk of developing asthma phage mannose receptor (Stein et al., 1992), the ␤-glu- (Laing et al., 1998). Interestingly, expression of CC16 can-receptor (Mosser and Handman, 1992), scavenger strongly inhibits both production and biologic activity receptor type I (Geng and Hansson, 1992), and CD163, a member of the scavenger receptor cysteine-rich family of interferon (IFN)-␥. Thus, proinflammatory reactions (Ho¨ gger et al., 1998). Despite this enhanced capacity are closely interconnected with counter-regulatory anti- for phagocytosis, alternatively activated macrophages inflammatory pathways. do not exert enhanced killing functions towards mi- In the regulation of immune-mediated as well as non- crobes. NO production, for example, is counteracted in specific inflammation, antigen-presenting cells such as alternatively activated macrophages by enhanced ex- mononuclear phagocytes and dendritic cells play a ma- pression of arginase, competing with NO synthases for jor role. In the past, research in inflammation biology has L-arginine as its substrate (Munder et al., 1998). Simi- focused on the proinflammatory actions of mononuclear larly, O2 production is suppressed in alternatively acti- phagocytes including phagocytosis, antigen processing, vated macrophages (Becker and Daniel, 1990). Thus, antigen presentation, T cell activation, and cytokine se- alternatively activated macrophages seem to be first- cretion. IFN␥ and bacterial lipopolysaccharides were iden- line defense cells that need not mount a strong Th1 tified as the major mediators of this classical macrophage immune response in order to function successfully. In addition, alternatively activated macrophages ex- * To whom correspondence should be addressed (e-mail: goerdt@ hibit enhanced expression levels of MHC class II mole- zedat.fu-berlin.de). cules such as HLA-DR and HLA-DQ, indicating that they Immunity 138

Figure 1. Differentiation of Alternatively Activated APC are prepared for effective antigen presentation. With protein (MIP)-1␣ (Cheung et al., 1990; Standiford et al., respect to immunoglobulin receptors, alternatively acti- 1993; Bonder et al., 1998). Secondly, alternatively activated macrophages display cell surface expression of vated macrophages are associated with a high degree the low-affinity Fc⑀ receptor (CD23); however, they do of vascularization in vivo and seem to be angiogenic in not express any of the three species of Fc␥ receptors vitro (Goerdt et al., 1993b; Kodelja et al., 1997). Further- (Becker and Daniel, 1990). Thus, it seems that alterna- more, phagocytosis of apoptotic cells leads to alternatively activated macrophages may be able both to in- tive activation and inhibition of proinflammatory cyto- duce differentiation of naive T cells into antigen-specific kine secretion in macrophages in an autocrine/paracrine T helper cells, presumably of the Th2 type, and to exert manner (Fadok et al., 1998). Thus, alternatively activated Th2-associated effector functions (Cua and Stohlman, macrophages are strategically well located and well 1997). equipped to substantially contribute to healing in sub- In order to identify alternatively activated macro- siding inflammatory reactions. phages in vivo, monoclonal antibodies specific for alternatively activated macrophages have been used, in- Suppressive Functions of Alternatively cluding monoclonal antibody RM3/1 directed against a Activated Macrophages glucocortiocid-inducible splice variant of the scavenger Immunosuppressive functions of macrophages have receptor CD163 (Ho¨ gger et al., 1998) and a monoclonal been first described by Herberman and colleagues in the antibody against MS-1 high molecular weight protein (Goerdt et al., 1991; Walsh et al., 1991). In the healthy organism, alternatively activated macrophages are pref- Table 1. Molecular Repertoire of Alternatively versus Classically erentially found in normal placenta and lung, where they Activated Macrophages function to protect the respective organ from unwanted Alternative Classical inflammatory or immune reactions (Mues et al., 1989). Activationa Activation Alternatively activated macrophages were also identi- Cytokines IL-1R antagonist IL-1 fied during the healing phase of acute inflammatory re- IL-10 IL-6 actions, in chronic inflammatory diseases such as rheu- IL-12 matoid arthritis and psoriasis, and in wound healing TNF␣ tissue (Goerdt et al., 1993a; Szekanecz et al., 1994; Chemokines DC-CK1/AMAC-1 MIP-1␣ Djemadji-Oudjiel et al., 1996). This distribution pattern Immune receptors Fc⑀RII (CD23s) Fc␥RI (CD64) Mph mannose R Fc␥RII (CD32) suggests that alternatively activated macrophages may Scavenger RI Fc␥RIII (CD16) participate in the three phases of healing, i.e., down- ␤-glucan R regulation of inflammation, angiogenesis, and elimina- CD163 (RM3/1) tion of tissue debris. With respect to downregulation of Killer molecules Arginase NO, iNOS inflammation, alternatively activated macrophages are O2 characterized by expression and synthesis of anti-inflam- a Regulation and expression of inflammation-associated macro- matory cytokines such as IL-10 and IL-1 receptor antag- phage molecules and genes are regulated antagonistically by IL-4 onist (Fenton et al., 1992; Schebesch et al., 1997); they and IFN␥, i.e., alternative macrophage molecules are induced by lack expression of proinflammatory cytokines such as IL-4 and inhibited by IFN␥, while classical macrophage molecules are induced by IFN␥ and inhibited by IL-4. IL-1, TNF␣, IL-6, IL-12, and macrophage inflammatory Review 139

mid-1970s (Oehler et al., 1977). Several lines of evidence APC and a specific T cell as a prerequisite to T cell indicate today that alternatively activated macrophage activation, expansion, and differentiation. However, ex- and suppressor macrophage populations may at least pression of DC-CK1 in alternatively activated macro- partially overlap. Placental macrophages, protecting the phages as well as in dendritic cells indicates that DC- immunologically privileged embryo, and alveolar macro- CK1 itself may not determine whether specific immunity phages, protecting the lung from unwanted environmen- or tolerance is induced; other molecular and phenotypic tally induced inflammation, are the prototype naturally traits of the particular APC may also be involved. occurring suppressor macrophages (Chang et al., 1993). The suppressive effectivity of alveolar macrophages is Modulation of Granuloma Immunity by Alternatively so strong that dendritic cell antigen presenting functions Activated Suppressor Macrophages in the lung may be totally suppressed (Holt et al., 1988). A good example of the balancing functions of alternatively Both placental and alveolar macrophages have been activated suppressor macrophages in inflammatory re- shown to be typical alternatively activated macrophage actions is provided by various models of granuloma forma- populations (Mues et al., 1989; Kodelja et al., 1998). With tion. During the initiation phase of a granuloma, first-line respect to experimentally derived suppressor macrophages, circumstantial evidence also indicates a close defense tissue macrophages and other injured cellular relationship to alternatively activated macrophages. Ex- tissue components secrete proinflammatory cytokines perimentally derived suppressor macrophages have (IL-1, TNF␣) and chemokines (MIP-1␣), activating endo- been preferentially investigated using antigen-indepen- thelial cells and attracting blood-derived macrophages dent processes in tumor-bearing animals or during cer- to the lesion. These early lesional macrophages then tain infections (Chang et al., 1988; Saha et al., 1994). start to synthesize granuloma initiation factors, among Antigen-specific suppressive actions of macrophages them homologs of the immunophilin gene family. In the have also been reported (Kirschmann et al., 1994). In phase of immune modulation, T cells secreting cyto- these model systems, IFN␥, the classical macrophage kines along the lines defined by the Th1 and Th2 dichot- activating cytokine, has been shown to directly inhibit omy induce disease susceptibility or resistance. In suppressor macrophage activity (Schmidt Pak et al., schistosomiasis (Stadecker and Villanueva, 1994), for 1995). Vice versa, alternatively activated macrophages example, rejection of eggs is primarily induced by large in vitro actively inhibit mitogen-induced proliferation of granulomas and is accompanied by a dominant Th1 peripheral blood lymphocytes and CD4ϩ T cells (Sche- immune response. During the course of the disease, the besch et al., 1997). These findings convincingly confirm newly developing granulomas are smaller and lack a that alternative activation generates immunosuppres- prominent T cell component. These late granuloma mac- sive macrophage populations. rophages strongly express IL-10 and induce clonal an- Besides the well known suppressive macrophage me- ergy in schistosoma egg antigen-specific Th1 cells while diators, i.e., PGE2 and lipocortin I, macrophage-derived supporting schistosoma egg antigen-specific Th2 cells. IL-10 and TGF␤ have been shown to exert downmodu- The Th1-suppressive activity of these granuloma macro- lating and anti-inflammatory effects. Other cytokines phages is so intense that they are even effective as with suppressive activity such as IL-16 and monoclonal efferent suppressor macrophages in preinfected synge- nonspecific suppressor factor (MNSF)-␤ have not been neic recipients (Villanueva et al., 1994). Thus, alterna- shown to be expressed by macrophages (Nakamura et tively activated macrophages might also act in alleviat- al., 1995), while ubiquitin cross-reactive protein (UCRP), ing disease activity or inducing tolerance in autoimmune which, like MNSF␤, belongs to the ubiquitin gene super- and allergic diseases despite established sensitization. family, is expressed upon classical activation. Since the proinflammatory cytokine macrophage migration inhibi- Induction of Tolerance by Alternatively Activated tory factor (MIF) may also be expressed by alternatively activated macrophages (Calandra et al., 1995), it seems Suppressor Macrophages that proinflammatory and anti-inflammatory actions are UVB-induced contact tolerance is another excellent finely balanced in either activation pathway. This may model for functional integration of all facets of suppres- hold true as well for a novel ␤-chemokine, dendritic cell- sive actions of alternatively activated macrophages. Con- derived CC-chemokine (DC-CK)1 (Adema et al., 1997), tact tolerance is a state of unresponsiveness to epicuta- which is also named alternative macrophage activation neously applied facultative contact allergens that is associated CC-chemokine (AMAC)-1 (Kodelja et al., 1998), thought to represent the physiological reaction to the that has recently been cloned from IL-4-treated antigen- environmental allergen thread. Contact tolerance is presenting cells. This new chemokine is highly homolo- maintained by continuous contact with low-dose anti- gous to MIP-1␣. In contrast to MIP-1␣, which is inducible gen or by UVB irradiation. While the APC mediating low- by classical macrophage mediators and is inhibited by dose contact tolerance are still elusive, UVB-induced IL-4 and glucocorticoids, its expression is specifically contact tolerance has been shown to be mediated by induced by alternative macrophage mediators such as alternatively activated macrophages (Stevens et al., IL-4, IL-13, and IL-10 and is inhibited by IFN␥. In vivo, 1995). UVB irradiation induces Langerhans cells to emi- alveolar macrophages, the prototype suppressor mac- grate from the epidermis into the dermis and further on rophages, and some lymphoid dendritic cells express to the regional lymph nodes. Subsequently, the epider- DC-CK1, while the prototype dendritic cells, i.e., epidermis is repopulated by CD36ϩCD11bϩCD1aϪ macro- mal Langerhans cells, do not. Functionally, it has been phages that express excessive amounts of IL-10, as well shown that DC-CK1 preferentially attracts naive CD4ϩ as TGF␤, but lack IFN␣ and -␤ (Knop et al., 1987). By T cells. Thus, DC-CK1 is a chemokine that may be in- secreting DC-CK1/AMAC-1, these UVB-induced alter- volved in bringing together an alternatively activated natively activated macrophages may attract CD8ϩ naive Immunity 140

Figure 2. Induction of Contact Tolerance by Alternatively Activated APC

T cells that are induced to differentiate into tolerogenic mediators of alternative activation are IL-4 and gluco- CD8ϩ T cells secreting Th2-associated cytokines such corticoids as well as IL-10. Functionally, alternatively as IL-4 and IL-10 (Tc2 cells) (Baadsgaard et al., 1988; activated APC are important players in downmodulating Steinbrink et al., 1996 ). Differentiation of Tc2 cells is inflammation and immunity. Alveolar and placental mac- dependent on CD4ϩ T cells and is mediated by their rophages are typical examples of naturally occuring, IL-2 production (Baadsgaard et al., 1988; Desvignes et alternatively activated macrophages; they represent al., 1996). IL-2-producing T helper cells are induced by first-line defense cells that, if they function successfully, alternatively activated macrophage-derived TGF␤; how- need not mount a strong Th1 immune response. Instead, ever, these T helper cells are defective in IL-2 receptor alternatively activated macrophages exert Th2-associ- ␣ chain expression and thus cannot develop into fully ated effector functions characterized by a high capacity mature effector Th1 cells (Stevens et al., 1995) (Figure 2). for endocytotic clearance and antigen presentation accompanied by reduced proinflammatory cytokine secre- Alternative Activation of Dendritic Cells tion. By secreting anti-inflammatory mediators such as Dendritic cells may also be alternatively activated and IL-10, PGE2, and other molecules yet to be identified, may be induced to exert suppressive effects. Transfer alternatively activated macrophages exert immuno- of pancreatic lymph node dendritic cells prevents auto- suppressive effects towards Th1-mediated immune re- immune diabetes in nonobese diabetic mice (Clare-Sal- actions. In concert with special chemokines such as zler et al., 1992). Alternative activation by IL-10 inhibits DC-CK1/AMAC-1, both alternatively activated macro- tumor antigen presentation by Langerhans cells (Beis- phages and dendritic cells may induce peripheral toler- sert et al., 1995). Alternative activation by IL-10 can ance towards self-components or environmental aller- furthermore induce cultured Langerhans cells to clonally gens. Thus, further clarification of alternative activation anergize antigen-specific Th1 cell lines, while their ac- pathways of APC and their effector molecules may help cessory cell functions towards Th2 cell lines are pre- develop novel immunotherapeutic strategies for chronic served (Enk et al., 1993). IL-10-treated immature den- inflammatory conditions including established autoim- dritic cells induce tolerance in naive T cells, and IL-10 mune and allergic diseases. To this end, it seems neces- induces tolerance in vivo (Steinbrink et al., 1997). In sary to direct a major effort toward dissecting the func- addition, untreated Langerhans cells stimulate Th1 cells, tional and molecular repertoire of alternatively activated while UVB-irradiated epidermal dendritic cells, similar APC and to test their integrated functions in elaborate to UVB-induced alternatively activated macrophages, animal models of human disease. induce Th2 cells and may mediate tolerance (Simon et al., 1990; Dai and Streilein, 1997). Acknowledgments

We would like to thank Drs. C. C. Geilen, S. Runkel, and N. Runkel Concluding Remarks for providing comments on this review. The concept of alternative immunologic activation of antigen-presenting cells has facilitated the understand- References ing of the often confusing results regarding the versatile Adema, G.J., Hartgers, F., Verstraten, R., de Vries, E., Marland, G., functions of APC in diverse experimental settings. Both Menon, S., Foster, J., Xu, Y., Nooyen, P., McClanahan, T., et al. the major APC populations, i.e., macrophages and den- (1997). A dendritic-cell-derived C-C chemokine that preferentially dritic cells, may be alternatively activated. Preferential attracts naive T cells. Nature 387, 713–717. Review 141

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