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(Journal of Leukocyte Biology. 2003;73:339-343.)
© 2003 by Society for Leukocyte Biology

Alerting and tuning the immune response by extracellular nucleotides

Andrea la Sala^*, Davide Ferrari, Francesco Di Virgilio, Marco Idzko, Johannes Norgauer and Giampiero Girolomoni

^* Immune Cell Interaction Unit, Mucosal Immunity Section, Laboratory of Clinical Investigation, NIAID, National Institutes of Health, Bethesda, Maryland;
Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Italy;
Department of Experimental Dermatology, University of Freiburg, Germany; and
Laboratory of Immunology, Istituto Dermopatico dell’Immacolata, IRCCS, Rome, Italy

Correspondence: Dr. Andrea la Sala, Immune Cell Interaction Unit, Mucosal Immunity Section, Laboratory of Clinical Investigation, NIAID, NIH, 10 Center Drive, 11/N214, Bethesda, MD 20892. E-mail: alasala{at}niaid.nih.gov

TOP ABSTRACT INTRODUCTION NUCLEOTIDES AS ENDOGENOUS DANGER... NUCLEOTIDE RECEPTORS EXTRACELLULAR NUCLEOTIDE-DC... EFFECTS OF NUCLEOTIDES ON... CONCLUSIONS REFERENCES

 
The interplay between pro- and anti-inflammatory mechanisms during inflammatory and immune responses is critical for avoiding excessive tissue damage. Extracellular nucleotides (e.g., adenosine 5'-triphosphate) may represent constitutive signals that can alert the immune system of abnormal cell death. Relatively high doses of nucleotides induce rapid release of proinflammatory mediators and favor pathogen killing. However, recent findings on antigen presenting cells, particularly dendritic cells, revealed a more complex role for these molecules. Chronic exposure to low-dose nucleotides can redirect cellular responses to prototypic activation stimuli, leading to suppressed inflammation and immune deviation.

Key Words: dendritic cell • monocyte • ATP • chemokine • IL-12

TOP ABSTRACT INTRODUCTION NUCLEOTIDES AS ENDOGENOUS DANGER... NUCLEOTIDE RECEPTORS EXTRACELLULAR NUCLEOTIDE-DC... EFFECTS OF NUCLEOTIDES ON... CONCLUSIONS REFERENCES

 
Secretion of proinflammatory cytokines such as interleukin (IL)-1 or tumor necrosis factor (TNF-) in response to invading microbial agents is an essential defense mechanism during first stages of infection but may be detrimental if inappropriately sustained. Therefore, the activity of mediators that down-regulate inflammation and immune responses is mandatory for a balanced response to infections and the prevention of excessive tissue damage. Mononuclear phagocytes and dendritic cells (DCs) play a major role in the initiation and regulation of innate and adaptive immunity. They are equipped with surface receptors for the recognition of many different types of pathogens. However, these cells can also directly react to tissue damage by recognition of constitutive or inducible endogenous "danger signals" provided by surrounding insulated cells [¹ , ² ]. Nucleotides that have reached the extracellular milieu can serve as danger molecules inducing antigen presenting cells (APCs) to initiate innate immunity by triggering the release of proinflammatory cytokines such as IL-1 and IL-6, cyclooxigenase-2 expression, superoxide generation, and favoring pathogen killing [³ , ⁴ ]. However, recent studies depicted a more complex role for extracellular nucleotides [in particular, adenosine 5'-triphosphate (ATP)] in the biology of APCs: Beyond activation, ATP exerts regulatory effects that influence the course of inflammatory reactions and the outcome of T cell-mediated immune responses. We propose that the presence of ATP in the pericellular environment favors an alternative activation of DCs and macrophages with altered cytokine and chemokine secretion as well as chemokine receptor expression, which leads to suppressed inflammation and immune deviation.

TOP ABSTRACT INTRODUCTION NUCLEOTIDES AS ENDOGENOUS DANGER... NUCLEOTIDE RECEPTORS EXTRACELLULAR NUCLEOTIDE-DC... EFFECTS OF NUCLEOTIDES ON... CONCLUSIONS REFERENCES

 
Endogenous-inducible danger signals are represented by molecules such as TNF-, IL-1ß, or CD40L, which are up-regulated during inflammation and deliver an activation stimulus to monocyte/macrophages and DCs. Constitutive molecules can signal danger as well. How can a molecule expressed in unperturbed conditions be a signal of tissue stress/injury? Substances that are normally confined inside cells can be released following tissue damage, and their increased, extracellular concentration can therefore be a simple sign of cell damage. However, for constitutive molecules to function as danger signals, they must be recognized by APCs. Nucleotides fulfill these requirements, as they are present at high concentration (5–10 mM) in the cytoplasm of all cells, whereas in the extracellular compartment, their concentration is in the nanomolar range. Thus, increased extracellular nucleotide concentration is likely to be associated with cell injury. Importantly, nucleotides are also released via nonlytic mechanisms through regulated transport: ATP has been reported to be secreted by different cell types in a broad variety of conditions such as shear stress, endotoxin stimulation, or at sites of platelet aggregation [^{5 6 7} ]. Nucleotides are recognized by P2 purinergic receptors (P2R) ubiquitously expressed on cell membrane throughout the human body, and a growing amount of data showed that activation of P2R can have a profound impact on immune cell functions.

TOP ABSTRACT INTRODUCTION NUCLEOTIDES AS ENDOGENOUS DANGER... NUCLEOTIDE RECEPTORS EXTRACELLULAR NUCLEOTIDE-DC... EFFECTS OF NUCLEOTIDES ON... CONCLUSIONS REFERENCES

 
P2R are subdivided into P2XR and the P2YR families, the former identified as multimeric ligand-gated plasma membrane ion channels and the latter, as seven-spanning G protein-coupled receptors [⁸ ]. In mammalian, P2XR and P2YR families are composed by seven members (P2X_1–7 and P2Y_{1,2,4,6,11–13}). The activation of P2XR by extracellular ATP leads to increased plasma membrane permeability to ions (Na⁺, K⁺, and Ca²⁺). The P2X₇ member differs from the others for its ability to undergo a progressive increase in size upon sustained stimulation that leads to the generation of a nonselective, reversible membrane pore, permeable to low-molecular weight hydrophilic solutes. P2YR triggering induces inositol triphosphate generation, Ca²⁺ release from intracellular stores, or adenylate cyclase stimulation/inhibition via activation of G proteins (G_i/o or G_q/11). The only known physiological ligand for P2XR is ATP, whereas the P2YR subtypes are differentially sensitive to various nucleotides: At P2Y₁, P2Y₁₂, and P2Y₁₃, the preferred agonist is adenosine 5'-diphosphate (ADP); at P2Y₂, ATP and uridine 5'-triphosphate (UTP) are equipotent; at P2Y₄, UTP is preferred; at P2Y₆, uridine 5'-diphosphate; whereas P2Y₁₁ is the only P2YR selective for ATP [⁹ ]. P2R-mediated responses are regulated by the local nucleotide concentration: P2X_1–6 have EC₅₀ in the low micromolar range and P2X₇ in the hundred micromolar range, whereas P2YR display higher affinity responding to nanomolar concentrations of the ligand. Another factor that modulates P2R-mediated responses is the extracellular nucleotide metabolism: ATP can be hydrolyzed to ADP by ecto-ATP/ADPase (CD39) and NTPDase2 (CD39L1) [¹⁰ ]. CD39, which can also hydrolyze ADP to adenosine 5'-monophosphate (AMP), is expressed on the membrane of a wide variety of cells such as Langerhans cells and DCs, macrophages, natural killer (NK) cells, activated B lymphocytes, and endothelial cells. In addition, AMP is the substrate for 5'-ectonucleotidase (CD73) leading to the generation of adenosine, which can activate P1 adenosine receptors (see inset in Fig. 1 ).

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Figure 1. Comparison between canonic and alternative DC maturation achieved in the presence of extracellular ATP. In the normal paradigm of DC maturation (a), activation signals, e.g., LPS, trigger DC early release of CCL2, CCL3, CCL4, CXCL10, and CCL5 recruiting circulating monocytes and other immature DCs. Mature DCs release TNF- and IL-12, which promote inflammation and NK cell activation, respectively. IFN- produced by infiltrating Th1 lymphocytes and NK cells acts as a positive feedback signal for IL-12 production. Myeloid DCs maturating in this environment migrate to lymph nodes and serve as a potent, natural adjuvant for type 1 T cell priming. (b) Extracellular ATP released by damaged cells acts as chemoattractant for immature DCs and blocks the production of IL-1, TNF-, and IL-12 as well as CXCL10 and CCL5 but not IL-10 from maturing DCs. Moreover, DCs exposed to ATP up-regulate costimulatory molecules and the receptors for lymphoid chemokines and down-regulate receptors for inflammatory chemokines, allowing a more prominent lymph node localization. The block of IL-12 production favors the generation of Th2 responses. Extracellular ATP metabolism by membrane ectoenzymes expressed by DCs (Inset). ATP is hydrolyzed to ADP and subsequently to AMP by apyrase (CD39). In turn, AMP is substrate for 5'-ectonucleotidase (CD73), leading to generation of adenosine (ADO), which binds P1 purinergic receptors (adenosine receptors).

TOP ABSTRACT INTRODUCTION NUCLEOTIDES AS ENDOGENOUS DANGER... NUCLEOTIDE RECEPTORS EXTRACELLULAR NUCLEOTIDE-DC... EFFECTS OF NUCLEOTIDES ON... CONCLUSIONS REFERENCES

 
The importance of the interaction between danger signals and DCs resides in the unique property of these cells to serve as sentinel for danger and as potent initiators of immune responses. DCs are a heterogeneous population of cells that circulate in the bloodstream or reside in the peripheral tissues in an immature state in which they are specialized in the uptake of potential antigens. Trafficking of DCs through tissues is strongly regulated by the level of chemokine receptor expression. Immature DCs and monocytes express receptors for inflammatory chemokines (CXCR1, CCR1, CCR2, and CCR5), which account for their capacity to migrate from blood to inflamed tissues where their cognate ligands are produced and where danger signals are likely to be present. To date, most information available on the effect of extracellular nucleotides on DC biology has been provided by studies on human DCs generated in vitro by cytokine treatment of blood monocytes. In this model, ATP acts as a chemoattractant for immature DCs [¹¹ ], and low concentrations (100 nM) of ATP induce calcium transients, actin polymerization, and chemotaxis in immature but not mature DCs through the activation of P2YR [¹² ]. It is interesting that CD39 null monocyte/macrophages, which have a lower capacity to metabolize extracellular ATP, display an impaired chemotactic response associated with P2YR-mediated signaling pathway desensitization [¹³ ].

In the current paradigm, DCs are initially induced to mature by different stimuli, such as to lipopolysaccharide (LPS), CpG oligonucleotides, viral RNA, and TNF-. Maturing DCs migrate from peripheral tissue to lymph nodes, where they present the antigen captured at the time and site of activation and deliver potent, instructive signals to naïve T lymphocytes, thus initiating an adaptive-immune response. DC maturation encompasses a coordinated down-regulation of inflammatory chemokine receptors (CCR1, 2, 5, and CXCR1) and induction of CCR7 and CXCR4. As a result, DCs lose sensitivity to inflammatory chemokines and acquire the ability to colocalize with naïve T cells in the lymph nodes (Fig. 1a) . ATP fosters this differentiation process and confers functional responsiveness to CCL19 and CXCL12, whereas chemotaxis to CCL4 is reduced, setting DCs for enhanced lymph node localization [¹⁴ ]. Maturing DCs on their way to lymph nodes up-regulate membrane expression of peptide-loaded major histocompatibility complex (MHC) molecules as well as costimulatory molecules and become very effective at activating naïve T cells. In turn, T cells further maturate DCs via CD40-CD40L interaction. At the initial stage of naïve T cell-DC interaction, the production of high levels of IL-12 by maturing DCs is pivotal in the preferential development of T helper cell type 1 (Th1) responses [¹⁵ ]. Moreover, IL-12 and TNF- released by DCs activate NK cells, which in turn, can reinforce IL-12 production by DCs by releasing interferon- (IFN-). The presence of ATP in the peripheral tissue may profoundly modify this picture. As shown in Figure 1b , ATP passively released from stressed or damaged cells induces an alternative pathway of DC maturation and monocyte/macrophage activation [¹⁶ , ¹⁷ ]. This is characterized by up-regulation of costimulatory membrane molecules but lack of production of IL-12 as well as inflammatory cytokines and chemokines; prototypical stimuli for DC maturation such as LPS and CD40L, in the presence of ATP, fail to induce production of IL-6, IL-1ß, TNF-, and IL-12, whereas the up-regulation of membrane molecules and of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist is unaffected. As a result of blocked IL-12 production, DCs matured in the presence of ATP have an impaired capacity to promote type 1 polarization of naïve T lymphocytes, favoring instead the development of type 2 lymphocytes [¹⁶ ]. Similarly, ATP selectively inhibits the production of IL-12 and TNF- by mouse macrophages and of IFN-, by splenocytes after stimulation with LPS [¹⁷ ].

DCs are also an important source of chemokines: Immature DCs constitutively release CCL22 and CCL17 [¹⁸ ]. At early stages of maturation, DCs produce high levels of chemokines, such as CCL2, CCL3, CCL4, CCL5, CXCL8, and CXCL10, which sustain the recruitment of circulating, immature DCs, monocytes, and T cells to inflamed tissue [¹⁹ ]. Lymphoid chemokines, including CCL19, CCL17, and CCL22, are produced or up-regulated later during DC maturation [¹⁹ , ²⁰ ], providing chemotactic signals for mature DCs and for T cells in secondary lymphoid organs. CCL19 attracts naïve T cells that express CCR7, whereas CCL17 and CCL22 act on naïve and recently activated type 2 T cells expressing CCR4 (Fig. 1a) [²¹ , ²² ]. ATP affects the pattern of chemokine release from DCs by up-regulating the constitutive production of CCL22 and inhibiting the LPS-induced secretion of CXCL10 and CCL5 [¹⁴ ]. This results in a selectively impaired capacity of DCs to recruit type 1 but not type 2 lymphocytes [¹⁴ ]. In fact, CCR5 and CXCR3 (which can be activated by CCL5 and CXCL10, respectively) are preferentially expressed by Th1 cells, whereas CCR4 (which is activated by CCL22 and CCL17) is more prominent on Th2 cells [²² ]. By diminishing DC capacity to attract IFN--producing lymphocytes, ATP may potently impair the amplification of a type 1 response and favor type 2 immunity.

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The in vivo relevance of P2R on DC functions has been recently brought to the attention by Mizumoto et al. [²³ ] who described the critical role of CD39 in the induction of T cell responses by skin Langerhans cells. T cell-mediated contact hypersensitivity to haptens is harshly attenuated in CD39^-/- mice. In addition, T cells increase ATP pericellular concentration upon activation, and CD39^-/- DCs display ATP unresponsiveness as a result of P2YR desensitization. These observations suggest that nucleotide-mediated communication between DCs and T cells involving P2YR represents an important event during antigen presentation in vivo. As a result of systemic side-effects, studies on the regulation of inflammation and immune responses by exogenous ATP administration have been scanty. However, in vivo studies using ATP analogs before injection of LPS showed inhibition of inducible nitric oxide synthase expression by macrophages as well as decreased serum levels of TNF- and IL-1, resulting in rescue from endotoxic death [²⁴ , ²⁵ ]. This raised the issue of a possible involvement of P2R in LPS-dependent signaling. LPS activates the Toll-like receptor (TLR)4 expressed by monocytes, macrophages, and DCs. TLR4 signaling pathway involves the adaptor molecule MyD88, which is responsible for the recruitment and activation of IL-1 receptor-associated kinase and TNF receptor-associated factor 6. The downstream event in this pathway is the activation and nuclear translocation of the transcription factor, nuclear factor-B, which is critical for the expression of IL-1, IL-12, TNF-, CCL5, and B7.1. It is interesting that LPS-induced maturation of DCs from MyD88-deficient mice is strikingly similar to that obtained in human DCs stimulated by LPS in the presence of ATP, with up-regulation of MHC and costimulatory molecules and blocked IL-12 and TNF- but not IL-10 production [²⁶ ]. It has been proposed that TLR4 triggering by LPS stimulates MyD88-dependent and -independent pathways, the first leading to cytokine production and the latter, to membrane maturation. It is therefore possible that P2R signaling induced by ATP might block the MyD88-dependent but not the MyD88-independent pathway of LPS-induced DC activation. If this is the case, the identification of specific agonists and inhibitors of individual P2R might represent a powerful tool for the treatment of septic shock and Th1-mediated autoimmune diseases. Recently, it has been proposed that the P2Y₁₁ receptor, which is coupled to adenylate cyclase activation, is involved in the ATP-induced maturation of DCs. Of note, other cyclic AMP (cAMP)-elevating factors block IL-12, TNF-, CCL5, and CXCL10 but not IL-10 and CCL22 induction by LPS [¹⁸ , ^{27 28 29 30 31} ]. When TNF- is used as maturation stimulus for DCs, up-regulation of costimulatory molecules occurs with slower kinetics, and IL-12 is not induced. Surprisingly, ATP in combination with TNF- induces IL-12 production by DCs through activation of P2Y₁₁ and elevation of intracellular cAMP [³² , ³³ ]. Although low (nanomolar) doses of ATP are chemotactic for immature DCs, and micromolar concentrations skew DC properties to a Th2-promoting activity, other studies have reported that high doses (millimolar) determine the opening of the P2X₇ channel-permeabilizing DC membrane. Human and mouse DCs express the P2X₇ receptor to a very high level not usually found in monocytes or other nonimmune cells [³⁴ , ³⁵ ], suggesting that high expression of this P2R could be a phenotypic marker of DCs. As a result of the availability of specific antibodies and inhibitors, P2X₇ is the best-characterized P2R, and its activation mediates the activatory effects of high ATP doses on innate immunity [³ , ⁴ ]. Conversely, the activation of P2X₇ may have a down-regulatory role on adaptive immune responses; indeed a striking functional correlate of high-level P2X₇ expression is the increased sensitivity to ATP-dependent cytotoxicity, which has been described to occur by necrosis or apoptosis depending on the dose [³⁴ , ³⁵ ]. Moreover, activated macrophages up-regulate P2X₇ expression, and it has been suggested that ATP released by cytotoxic T lymphocyte cells during antigen presentation mediates their lysis, thus down-regulating immune response [³⁶ ].

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We propose a model of purinergic receptor activation by ATP during the initiation of immune response that affects DC and macrophage biology at multiple levels. Increasing concentration gradient of extracellular ATP attracts immature DCs. In the proximity of damaged cells where the concentration may be in the micromolar range, ATP blocks the synthesis of proinflammatory cytokines by DCs and their capacity to promote the Th1 response, favoring the development of type 2 responses, which may be less harmful. Finally, in the lymph node, T cell priming may be terminated by the toxic effects of ATP released by activated T cells on APCs via the P2X₇. Further studies on the functional expression of P2R in vivo by different DC subsets may give important insight on the potential application of targeting P2R to manipulate inflammatory and immune responses.

 
The Authors thank Dr. Brian Kelsall for helpful discussions and support.

Received August 27, 2002; revised September 17, 2002; accepted September 27, 2002.

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