Introduction

The single Platelet-activating Factor receptor (PAFR) is a G-protein coupled receptor present in the plasma and nuclear membranes of the majority of cells of the vascular and innate immune system that activates a variety of pathways involved in inflammation, oncogenic transformation, tumor growth, angiogenesis and metastasis. PAFR also induces more physiological responses, including human reproduction and gas exchange in the lung (reviewed in [21,50,54,68]). The gene encoding this protein in humans is named PTAFR, is mapped to chromosome 1, and alternative splicing results in multiple transcript variants [22]. Binding of PAF or it mimics (oxidized short-chain phosphatidylcholine species) to the PAFR stimulates numerous signal transduction pathways including phospholipases C, D, A₂, mitogen-activated protein kinases (MAPKs), and the phosphatidylinositol-calcium second messenger system. Following PAFR activation, cells rapidly desensitize from PAFR phosphorylation and internalization. Additional functions for PAFR suggest a pivotal role in macrophage resistance to infection and vascular inflammation. Several clinically tested PAFR antagonists are available and could be therapeutically useful despite of their failure in treating asthma.

Cell signalling downstream PAFR activation

PAFR is widely expressed, including in cells of the immune system (e.g., neutrophils, eosinophils, mast cells, macrophages, B cells) as well as in other cell types (e.g., keratinocytes, fibroblasts, platelets). Creation of PAFR knockout mice has confirmed that a single receptor mediates PAF effects [24]. Two different PAFR mRNA transcripts with open identical reading frames are generated through the use of separate promoters. Expression of transcript I is regulated by estrogen, and transcript II is regulated by the PKC-NFkB pathway. Consistent with the ability of the PAFR to activate a myriad of responses, this receptor is coupled to G proteins Gi, Gq, and G12/13. In addition, the PAFR has been demonstrated to transactivate the epidermal growth factor (EGF) receptor through its ability to release heparin-binding EGF [37]. Activation of the PAFR results in intracellular calcium mobilization, activation of mitogen-activated protein kinases, NF-kB pathway activation, and inhibition of cyclic AMP formation. In addition to PAFR effects alone, activation of the PAFR will synergize with other stimuli ranging from ultraviolet radiation to retinoids and other agents [3,37]. A mutant PAFR has been discovered whereby the alanine residue at position 224 is substituted by aspartic acid (A224D) in the putative third intracellular loop. This mutation which has diminished signaling ability but no discernible clinical effect is observed at a 7.8% allele frequency in Japanese populations [16,65]. Subsequently in European populations several other SNPs were discovered [43]; however these new polymorphisms of the PTAFR gene were not related to any clinical phenotype in a prospective cohort of coronary artery heart disease patients as compared to healthy controls (AtheroGene) [43].

PAFR agonists production

The term “Platelet-activating Factor” was first described as an activity released from activated basophils which induced platelet aggregation [4]. PAF usually denotes a 1-alkyl-2-acetyl glycerophosphocholine. The enzymatic synthesis is via either a remodeling pathway involving a phospholipase A₂ to remove an unsaturated fatty acid from ether choline phospholipid with an acetyltransferase adding acetyl-CoA, or through a de novo pathway whereby a phosphocholine moiety is adducted to a 1-alkyl-2-acetyl glycerol by a phosphocholine transferase [55,57]. In addition to these tightly controlled enzymatic pathways, PAFR agonists can be produced by unregulatedfree radical-mediated processes [29,42,49]. Esterified polyunsaturated fatty acids, especially arachidonate esterified at the sn-2 position of parent glycerophosphocholine are susceptible to oxidation due to the presence of bisallylic hydrogens, which serve as hydrogen donors for radical attack. Oxidation of esterified fatty acyl residues introduces oxy functions, rearranges bonds and fragments carbon-carbon bonds by β-scission to generate a myriad of reaction products. Among these are a series of phospholipids with oxidatively fragmented sn-2 acyl residues that terminate with either an ω-oxy function or a methyl group. If the oxidatively modified sn-2 acyl residue is a 1-alkyl choline phospholipid, then the resultant products can act as potent PAFR or peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists [11]. Pro-oxidative stressors that produce these PAFR agonists (oxidized GPC, PAF-like lipids) include cigarette smoke [32] and ultraviolet B radiation [36]. In addition to PAF and Ox-GPCs, other ligands including the gram-positive bacterial product lipotechoic acid have been reported to activate the PAFR [10,33,70].

PAFR in inflammation and immunity

PAFR is expressed in inflammatory and innate immunity cells. Its activation by agonists induces production of pro- and anti-inflammatory cytokines/mediators. It also induces eicosanoids and PAF production [21]. The cellular response to PAFR activation seems to depend on the type of G protein linked to the receptor [21]. Since the cellular membrane PAFR is coupled to Gq and the nuclear membrane receptor to Gi/o it can trigger distinct signaling pathways and it was suggested that the activation of the cell membrane receptor would generate early pro-inflammatory responses and synthesis of PAF which would in turn activate nuclear PAFR to induce transcription of genes for cytokines, COX2, iNOS [38]. During infections, production of PAF was shown to mediate resistance to L. amazonensis [34], T. cruzi [1] and K. pneumoniae [58] infection and PAFR antagonists were shown to increase the local and systemic infection. PAFR KO mice infected with T. cruzi present higher blood parasitemia, parasite load in lymph nodes and spleen and higher mortality [60]. Concomitant activation of PAFR and TLRs was shown to have pro-inflammatory effects [31] and association of PAFR with scavenger receptors that recognize oxidized molecules in the membranes of apoptotic cells or extracellular oxLDL particles, induce an anti-inflammatory response [12,14]. Thus, it seems that PAFR can act in cooperation with other macrophage receptors inducing either suppression or activation, affecting both innate and adaptive immunity [31]. Moreover, PAF and PAFR are components of acute inflammation [39], graft-versus-host disease [6] and in some chronic conditions including experimental cerebral malaria [30] and necrotizing enterocholitis [35].

PAFR in cutaneous biology

Keratinocytes, the most numerous cell type in the skin, synthesize PAF [41,63] and express functional PAFR linked to production of numerous cytokines [62]. The phenotype of mice overexpressing the PAFR includes spontaneous dermatitis and melanocytic neoplasms [25]. PAF has been implicated in disparate inflammatory skin disorders ranging from urticaria [19] to psoriasis [26,56]. In regards to the latter, in a murine model of psoriatic inflammation, PAF was identified in the skin lesions, and localized injection of PAF into skin worsened, and use of systemic PAFR antagonists improved the skin inflammation [56]. Finally, consistent with a potential role of PAF in psoriasis, recent studies indicate that dendritic cell PAFR activation polarizes T cells towards T-helper17 differentiation [13]. The PAFR also appears to be involved in how skin responds to exogenous stressors. Ultraviolet B radiation (290-320 nm; UVB) is a pro-oxidative stressor which has been the most studied. UVB stimulates the production of PAF and oxidized glycerophosphocholines (Ox-GPC) with PAFR agonistic activity [36]. PAFR signaling is involved in two separate aspects of photobiology. First, PAFR activation appears important in the early acute responses of UVB. In a murine model of photosensitivity due to deficiency of the DNA repair enzyme xeroderma pigmentosum type A (XPA), UVB treatment results in increased levels of PAF and Ox-GPC formation. Moreover, the exaggerated pro-inflammatory response to UVB in XPA-deficient mice is blocked by PAFR antagonists [67]. It should be noted that PAFR-deficient mice exhibit decreased acute inflammation as well as decreased production of cytokines such as tumor necrosis factor in response to UVB [61,67]. Second, the systemic immunosuppression induced by UVB has been demonstrated to involve PAFR signaling via Ox-GPCs [64,71]. Systemic PAFR antagonists inhibit tumor formation in a murine model of UVB photocarcinogenesis [59]. Other agents such as organic solvents found in jet fuel have also been demonstrated to act upon the skin to induce systemic immunosuppression via PAF/Ox-GPC PAFR agonists [52]. Thus, PAFR signaling appears to play an important role in inflammatory processes in the skin, and this system can be activated by a wide range of pro-oxidative stressors.

PAFR in tumour growth

The role of PAF/PAFR in tumors has been investigated in recent years. PAF has been associated to early malignant transformation in BRCA1-mutant epithelial ovarian cells [69], and melanocytic tumorigenesis was observed in transgenic mice over-expressing PAFR [25]. There are also suggestions of PAFR involvement in tumor metastasis and PAFR antagonists decreased lung metastasis in murine melanoma [23,40]. In human breast cancer, antagonists of PAFR inhibited cell proliferation in vitro and tumor growth [7,17]. PAFR antagonists reduced the progression of Ehrlich ascitis tumor and melanoma B16F10 [12,15]. Some tumor cell lines express PAFR and its activation induces anti-apoptotic factors [20]. Addition of PAF to melanoma Skmel37 cells in vitro, protected them from death induced by cisplatin and a PAFR antagonist enhanced cisplatin-induced cell death in the presence of PAF [48]. During tumor growth, as the number of tumor cells increases, many cells die by apoptosis or necrosis. There is evidence that apoptotic cells contribute to tumor progression by mechanisms involving PAFR. It was clearly demonstrated that subcutaneous co-injection of apoptotic cells together with a sub-tumorigenic dose of melanoma B16F10 cells in mice promotes tumor growth and that the tumour growth promoting effect of apoptotic cells is inhibited by PAFR antagonists [2]. Chemotherapy is another way of increasing the number of apoptotic cells in tumor microenvironment. Some tumor cell lines express PAFR and its activation induces up- regulation of anti-apoptotic factors such as Bcl-2, thus attenuating the cytotoxic effect of chemoterapic agents [20]. Addition of PAF to melanoma Skmel37 cells in vitro, protected them from death induced by cisplatin and a PAFR antagonist enhanced cisplatin-induced cell death in the presence of PAF [48]. Combined therapy with dacarbazine and a PAFR antagonist reduced melanoma growth and improved overall survival Tumor microenvironment elements such as microvascular density and number of suppressor macrophages within the tumor were among the targets of the combination therapy [12]. Combination of cisplatin and a PAFR antagonist also reduced melanoma progression in mice [48]. Thus, PAFR-dependent pathways are activated during experimental tumor growth, modifying the microenvironment and the phenotype of the tumor macrophages in such a way as to favor tumor growth and combination therapy with a PAFR antagonist and a chemotherapeutic drug may represent a promising strategy for the treatment of some tumors.

PAFR in atheroschlerosis and vascular inflammation

Oxidation of low density lipoproteins is an initial step of atherogenesis that generates proinflammatory phospholipids, PAF and its analogs that signal through PAFR [9,51]. These molecules are degraded by PAF-acetylhydrolase (PAF-AH) also called lipoprotein-associated PLA2 (Lp-PLA2), a circulating enzyme having both pro- and anti-inflammatory activities [28]. PAFR is expressed in human atherosclerotic plaques, mostly in macrophages and foam cells [5]. In macrophages, oxidized phospholipids present in both oxidized lipoproteins and in apoptotic cells interact with PAFR inducing immune suppression via PGE₂ and IL10 production [12,14]. There is evidence that PAFR and the scavenger receptor CD36 act cooperatively in the macrophage response to oxidized lipoproteins [53]; however there is no genetic proof of PAFR involvement in cardiovascular disease in Caucasians as the polymorphisms of this gene were not related to any phenotype in a prospective cohort of coronary artery heart disease patients as compared to healthy controls (AtheroGene) [43]. However, a DNA variant in the human PAFR gene, which substitutes an aspartic acid for an alanine residue at position 224 (A224D) in the putative third cytoplasmic loop was observed in a Japanese population at an allele frequency of 7.8% [16]. The functional consequences of this structural alteration suggested from the cellular in vitro studies that this naturally occurring mutation exhibits impaired coupling of PAFR to G-proteins and may be a basis for inter-individual variation in PAFR related physiological responses, disease predisposition or phenotypes, and drug responsiveness [16].

PAFR in reproduction

PAFR is present within most tissues involved in male and female reproduction and has critical roles in the normal function of spermatazoa, the preimplantation embryo and the female reproductive tract. PAF is also produced in each of these tissues. Upon ejaculation the mammalian spermatozoon produces PAF which acts in an autocrine manner on a sperm PAFR and this action induces capacitation (final maturation of sperm for fertilisation) [66]. Upon fertilisation an initial response of the new zygote is the de novo synthesis of PAF which is then released and bound by extracellular albumin [44]. This PAF acts back on the PAFR present on the membrane of the early embryo in an autocrine manner to cause the activation of the 1-o-phosphatidylinositol-3-kinase signalling pathway within embryo cells [45]. Activation of this pathway is essential for normal embryo development and it activates calcium/calmodulin/calmodulin-dependent kinase and AKT (protein kinase B)-dependent downstream signalling [46]. PAFR signalling acts to initiate the activation of transcription from the new embryonic genome and thus serves as a mechanism for the transition from maternal to embryonic control of development [27]. It also generates a survival response within embryo cells [47]. In particular, it serves to induce the latency of P53 action within embryo cells and this is essential for continued embryo development [18]. Within the reproductive tract, PAF acting on the PAFR causes pulsatile release of PGF2α and this acts as a luteolytic (causes the regression of the corpus luteum) mediator [8]. The presence of the embryo in the uterus prevents generation of luteolytic PGF2α. In each of these settings the PAFR acts in concert with a range of other ligand-receptors. As a consequence the absence of the PAFR has only a limited reproductive phenotype.

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