Chemosensory Cell-Derived Acetylcholine Drives Tracheal Mucociliary Clearance in Response to Virulence-Associated Formyl Peptides.

Mucociliary clearance through coordinated ciliary beating is a major innate defense removing pathogens from the lower airways, but the pathogen sensing and downstream signaling mechanisms remain unclear. We identified virulence-associated formylated bacterial peptides that potently stimulated ciliary-driven transport in the mouse trachea. This innate response was independent of formyl peptide and taste receptors but depended on key taste transduction genes. Tracheal cholinergic chemosensory cells expressed these genes, and genetic ablation of these cells abrogated peptide-driven stimulation of mucociliary clearance. Trpm5-deficient mice were more susceptible to infection with a natural pathogen, and formylated bacterial peptides were detected in patients with chronic obstructive pulmonary disease. Optogenetics and peptide stimulation revealed that ciliary beating was driven by paracrine cholinergic signaling from chemosensory to ciliated cells operating through muscarinic M3 receptors independently of nerves. We provide a cellular and molecular framework that defines how tracheal chemosensory cells integrate chemosensation with innate defense.

The Crosstalk between N-Formyl Peptide Receptors and uPAR in Systemic Sclerosis: Molecular Mechanisms, Pathogenetic Role and Therapeutic Opportunities.

Systemic Sclerosis (SSc) is a heterogeneous autoimmune disease characterized by widespread vasculopathy, the presence of autoantibodies and the progressive fibrosis of skin and visceral organs. There are still many questions about its pathogenesis, particularly related to the complex regulation of the fibrotic process, and to the factors that trigger its onset. Our recent studies supported a key role of N-formyl peptide receptors (FPRs) and their crosstalk with uPAR in the fibrotic phase of the disease. Here, we found that dermal fibroblasts acquire a proliferative phenotype after the activation of FPRs and their interaction with uPAR, leading to both Rac1 and ERK activation, c-Myc phosphorylation and Cyclin D1 upregulation which drive cell cycle progression. The comparison between normal and SSc fibroblasts reveals that SSc fibroblasts exhibit a higher proliferative rate than healthy control, suggesting that an altered fibroblast proliferation could contribute to the initiation and progression of the fibrotic process. Finally, a synthetic compound targeting the FPRs/uPAR interaction significantly inhibits SSc fibroblast proliferation, paving the way for the development of new targeted therapies in fibrotic diseases.

Amyloid beta and its naturally occurring N-terminal variants are potent activators of human and mouse formyl peptide receptor 1.

Formyl peptide receptors (FPRs) may contribute to inflammation in Alzheimer's disease through interactions with neuropathological Amyloid beta (Aß) peptides. Previous studies reported activation of FPR2 by Aß1-42, but further investigation of other FPRs and Aß variants is needed. This study provides a comprehensive overview of the interactions of mouse and human FPRs with different physiologically relevant Aß-peptides using transiently transfected cells in combination with calcium imaging. We observed that, in addition to hFPR2, all other hFPRs also responded to Aß1-42, Aß1-40, and the naturally occurring variants Aß11-40 and Aß17-40. Notably, Aß11-40 and Aß17-40 are very potent activators of mouse and human FPR1, acting at nanomolar concentrations. Buffer composition and aggregation state are extremely crucial factors that critically affect the interaction of Aß with different FPR subtypes. To investigate the physiological relevance of these findings, we examined the effects of Aß11-40 and Aß17-40 on the human glial cell line U87. Both peptides induced a strong calcium flux at concentrations that are very similar to those obtained in experiments for hFPR1 in HEK cells. Further immunocytochemistry, qPCR, and pharmacological experiments verified that these responses were primarily mediated through hFPR1. Chemotaxis experiments revealed that Aß11-40 but not Aß17-40 evoked cell migration, which argues for a functional selectivity of different Aß peptides. Together, these findings provide the first evidence that not only hFPR2 but also hFPR1 and hFPR3 may contribute to neuroinflammation in Alzheimer's disease through an interaction with different Aß variants.

Structural and conformational studies of biased agonism through formyl peptide receptors.

G protein-coupled chemoattractant receptors are class A GPCRs that couple primarily to the Gi class of heterotrimeric G proteins. Initially identified for their abilities to mediate leukocyte chemotaxis, chemoattractant GPCRs such as the formyl peptide receptors (FPRs) have been known for their diverse cellular functions in response to a variety of agonists. Stimulation of FPR2, in particular, leads to ligand-dependent activation of proinflammatory signaling as well as anti-inflammatory and proresolving signaling. Recently, the structures of FPR2-Gi protein complexed with ligands of different compositions have been solved by crystallization and cryo-electron microscopy. Analysis of the structural data as well as molecular simulation has led to the findings that the FPR2 binding pocket is sufficiently large for accommodation of several different types of ligands but in different poses. This mini-review focuses on the structural and conformational aspects of FPR2 for mechanisms underlying its biased agonism.

Annexin-A1: The culprit or the solution?

Annexin-A1 has a well-defined anti-inflammatory role in the innate immune system, but its function in adaptive immunity remains controversial. This glucocorticoid-induced protein has been implicated in a range of inflammatory conditions and cancers, as well as being found to be overexpressed on the T cells of patients with autoimmune disease. Moreover, the formyl peptide family of receptors, through which annexin-A1 primarily signals, has also been implicated in these diseases. In contrast, treatment with recombinant annexin-A1 peptides resulted in suppression of inflammatory processes in murine models of inflammation. This review will focus on what is currently known about annexin-A1 in health and disease and discuss the potential of this protein as a biomarker and therapeutic target.

Association of Fpr1 gene expression with osteogenesis and adipogenesis of adipose derived stem cells.

Formyl peptide receptors (Fprs) play fundamental roles in multiple cell functions including promotion of osteogenesis and bone fracture healing. In this study, the role of Fpr1 gene in osteogenic and adipogenic differentiation of adipose derived stem cells (ADSCs) was investigated. Primary ADSCs (mADSCs) from either Fpr1 knockout (KO) or wild type (WT) mice and human ADSCs (hADSCs) were treated by osteogenic (OM) or adipogenic (AM) medium, with basal medium as control. Osteogenesis and adipogenesis were measured by histological and biochemical methods. In both hADSCs and mADSCs, Fpr1 gene expression, osteogenic gene expression, as well as mineralization were increased after osteogenic induction. The osteogenic capacity of KO ADSCs was remarkably reduced compared to WT ADSCs, with decreased levels of expression of osteogenic markers, alkaline phosphatase activity, and mineralization. In contrast, the adipogenesis of KO ADSCs was remarkably enhanced compared with WT ADSCs, forming more lipid droplets, and increasing expression of adipogenic markers PPARγ and aP2. Expression of the nuclear transcription factor Forkhead box protein O1 (FoxO1) was decreased in KO ADSCs, while OM and AM caused increase and decrease in FoxO1 expression, respectively. The current study revealed a correlation of Fpr1 gene expression with osteogenesis and adipogenesis of mADSCs, underlying a mechanism involving FoxO1. Our present research suggests that targeting Fpr1 might be a novel strategy to enhance osteogenesis of ADSCs.

The Role of Formyl Peptide Receptors in Permanent and Low-Grade Inflammation: Helicobacter pylori Infection as a Model.

Formyl peptide receptors (FPRs) are cell surface pattern recognition receptors (PRRs), belonging to the chemoattractant G protein-coupled receptors (GPCRs) family. They play a key role in the innate immune system, regulating both the initiation and the resolution of the inflammatory response. FPRs were originally identified as receptors with high binding affinity for bacteria or mitochondria N-formylated peptides. However, they can also bind a variety of structurally different ligands. Among FPRs, formyl peptide receptor-like 1 (FPRL1) is the most versatile, recognizing N-formyl peptides, non-formylated peptides, and synthetic molecules. In addition, according to the ligand nature, FPRL1 can mediate either pro- or anti-inflammatory responses. Hp(2-20), a Helicobacter pylori-derived, non-formylated peptide, is a potent FPRL1 agonist, participating in Helicobacter pylori-induced gastric inflammation, thus contributing to the related site or not-site specific diseases. The aim of this review is to provide insights into the role of FPRs in H. pylori-associated chronic inflammation, which suggests this receptor as potential target to mitigate both microbial and sterile inflammatory diseases.

Caulerpin Mitigates Helicobacter pylori-Induced Inflammation via Formyl Peptide Receptors.

The identification of novel strategies to control Helicobacter pylori (Hp)-associated chronic inflammation is, at present, a considerable challenge. Here, we attempt to combat this issue by modulating the innate immune response, targeting formyl peptide receptors (FPRs), G-protein coupled receptors that play key roles in both the regulation and the resolution of the innate inflammatory response. Specifically, we investigated, in vitro, whether Caulerpin-a bis-indole alkaloid isolated from algae of the genus Caulerpa-could act as a molecular antagonist scaffold of FPRs. We showed that Caulerpin significantly reduces the immune response against Hp culture filtrate, by reverting the FPR2-related signaling cascade and thus counteracting the inflammatory reaction triggered by Hp peptide Hp(2-20). Our study suggests Caulerpin to be a promising therapeutic or adjuvant agent for the attenuation of inflammation triggered by Hp infection, as well as its related adverse clinical outcomes.

Pyridinone Derivatives as Interesting Formyl Peptide Receptor (FPR) Agonists for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week.

Copper regulates the interactions of antimicrobial piscidin peptides from fish mast cells with formyl peptide receptors and heparin.

Phagocytic cells in fish secrete antimicrobial peptides (AMPs) such as piscidins, glycosaminoglycans such as heparin, and copper ions as first-line immune defenses. Recently, we established that Cu2+ coordination by piscidins 1 (P1) and 3 (P3) enhances their antibacterial activity against membranes and DNA. Interestingly, we noted that physicochemical similarities exist between both piscidins and other AMPs that interact with heparin and induce immune-cell chemotaxis through formyl peptide receptors (FPRs) involved in innate immunity. Thus, we postulated that P1 and P3 interact with heparin and FPRs but that these interactions distinctively depend on Cu2+ Here, we investigate the interactome potentiated by piscidins, heparin, FPR, and Cu2+ Utilizing FPR-transfected cells and neutrophils, we demonstrate that both piscidins exclusively use FPR1 and FPR2 to induce chemotaxis and that Cu2+ reduces their chemotaxis induction. P1 is more effective at activating FPR1 than P3 and other known AMP ligands. Furthermore, the expression of Fpr2 on the surface of neutrophils is down-regulated by both peptides. Copper conjugation of the peptides does not further increase down-regulation, suggesting that the conformational changes induced by the metal translate into reduced FPR efficacy without altering the binding affinity. Using surface plasmon resonance, we show that piscidin-heparin interactions are Cu2+-dependent and reduced at the acidic pH of phagosomes. Although heparin decreases the antimicrobial activity of P3-Cu2+, it does not affect bacterial killing by P1-Cu2+ Copper's effects on modulating the micromolar-range interactions of both piscidins with FPR and heparin suggest that the interactome of these distinct immune agents plays an important role in innate immunity. The interactions between diverse host-defense molecules uncovered here may help inform the design of novel therapeutics to treat immune-related diseases.

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors.

Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.

New perspectives in cancer: Modulation of lipid metabolism and inflammation resolution.

Inflammation is considered an enabling feature of cancer. Besides the persistence of inflammatory stimuli, also defective mechanisms of resolution can lead to chronic inflammation. Inflammation resolution is an active process controlled by lipidic specialized pro-resolving mediators (SPMs), derived from ω-3 or ω-6 essential polyunsaturated fatty acids (PUFA) through the activity of lipoxygenases (ALOX5 and 15). Thus, a lack or defect in resolution mechanisms may affect cancer development and progression by prolonging inflammation. Components of pro-resolving pathways (PUFA, enzymes, or SPMs) have been reported to modulate various cancer features by affecting both cancer cells and cancer-associated stroma. Here, we will review the most important mechanisms by which SPMs, ω-3/6 PUFA, and ALOXs affect cancer biology, paying particular attention to their role in the inhibition of inflammation and angiogenesis, two of the most important hallmarks of cancer. The collection of these results may suggest novel perspectives in cancer management based on the modulation of lipid metabolism and the production of SPMs.

Therapeutic Potential of Annexin A1 in Ischemia Reperfusion Injury.

Cardiovascular disease (CVD) continues to be the leading cause of death in the world. Increased inflammation and an enhanced thrombotic milieu represent two major complications of CVD, which can culminate into an ischemic event. Treatment for these life-threatening complications remains reperfusion and restoration of blood flow. However, reperfusion strategies may result in ischemia-reperfusion injury (I/RI) secondary to various cardiovascular pathologies, including myocardial infarction and stroke, by furthering the inflammatory and thrombotic responses and delivering inflammatory mediators to the affected tissue. Annexin A1 (AnxA1) and its mimetic peptides are endogenous anti-inflammatory and pro-resolving mediators, known to have significant effects in resolving inflammation in a variety of disease models. Mounting evidence suggests that AnxA1, which interacts with the formyl peptide receptor (FPR) family, may have a significant role in mitigating I/RI associated complications. In this review article, we focus on how AnxA1 plays a protective role in the I/R based vascular pathologies.

Radiosynthesis and in vivo Evaluation of Carbon-11 (2S)-3-(1H-Indol-3-yl)-2-{[(4-methoxyphenyl)carbamoyl]amino}-N-{[1-(5-methoxypyridin-2-yl)cyclohexyl]methyl}propanamide: An Attempt to Visualize Brain Formyl Peptide Receptors in Mouse Models of Neuroinflammation.

Here, we describe the very first attempt to visualize in vivo formyl peptide receptors (FPRs) in mouse brain by positron emission tomography (PET). FPRs are expressed in microglial cells where they mediate chemotactic activity of ß-amyloid peptide in Alzheimer disease and, thus, are involved in neuroinflammatory processes. To this purpose, we have selected (2S)-3-(1H-Indol-3-yl)-2-{[(4-methoxyphenyl)carbamoyl]amino}-N-{[1-(5-methoxypyridin-2-yl)cyclohexyl]methyl}propanamide ((S)-1), that we have previously identified as a potent non-peptidic FPR agonist. (S)-[(11) C]-1 has been prepared in high radiochemical yield. (S)-[(11) C]-1 showed very low penetration of blood-brain barrier and, thus, was unable to accumulate into the brain. In addition, (S)-[(11) C]-1 was not able to label FPRs receptors in brain slices of PS19 and APP23 mice, two animal models of Alzheimer disease. Although (S)-[(11) C]-1 was not suitable to visualize FPRs in the brain, this study provides useful information for the design and characterization of future potential PET radioligands for visualization of brain FPRs by PET.

Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.

Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2.

Convergence of FPR-rs3-expressing neurons in the mouse accessory olfactory bulb.

In the mouse, most members of the FPR receptor family are expressed by vomeronasal sensory neurons. The neural circuitry corresponding to this class of chemical sensors is unknown. Taking advantage of the presence of FPR-rs3 on both vomeronasal dendrites and axonal fibers, we visualized the distribution of sensory cells expressing this member of the FPR family, and their corresponding axonal projections in the olfactory bulb. We found a rostrocaudal gradient of receptor choice frequency in the vomeronasal sensory neuroepithelium, and observed a convergence of FPR-rs3 axons into multiple, linked and deeply located glomeruli. These were homogenously innervated, and spatially restricted to the basal portion of the rostral accessory olfactory bulb. This organization, reminiscent of the one that characterizes axonal projections of V1R-expressing neurons, supports a role played by these receptors in the perception of semiochemicals.

Differential requirement of Formyl Peptide Receptor 1 in macrophages and neutrophils in the host defense against Mycobacterium tuberculosis Infection.

Formyl peptide receptors (FPR), part of the G-protein coupled receptor superfamily, are pivotal in directing phagocyte migration towards chemotactic signals from bacteria and host tissues. Although their roles in acute bacterial infections are well-documented, their involvement in immunity against tuberculosis (TB) remains unexplored. This study investigates the functions of Fpr1 and Fpr2 in defense against Mycobacterium tuberculosis (Mtb), the causative agent of TB. Elevated levels of Fpr1 and Fpr2 were found in the lungs of mice, rabbits and peripheral blood of humans infected with Mtb, suggesting a crucial role in the immune response. The effects of Fpr1 and Fpr2 deletion on bacterial load, lung damage, and cellular inflammation were assessed using a TB model of hypervirulent strain of Mtb from the W-Beijing lineage. While Fpr2 deletion showed no impact on disease outcome, Fpr1-deficient mice demonstrated improved bacterial control, especially by macrophages. Bone marrow-derived macrophages from these Fpr1 -/- mice exhibited an enhanced ability to contain bacterial growth over time. Contrarily, treating genetically susceptible mice with Fpr1-specific inhibitors caused impaired early bacterial control, corresponding with increased bacterial persistence in necrotic neutrophils. Furthermore, ex vivo assays revealed that Fpr1 -/- neutrophils were unable to restrain Mtb growth, indicating a differential function of Fpr1 among myeloid cells. These findings highlight the distinct and complex roles of Fpr1 in myeloid cell-mediated immunity against Mtb infection, underscoring the need for further research into these mechanisms for a better understanding of TB immunity.

Knockout of formyl peptide receptor 1 reduces osteogenesis and bone healing.

AIMS: Formyl peptide receptor 1 (FPR1), from a G-protein coupled receptor family, was previously well-characterized in immune cells. But the function of FPR1 in osteogenesis and fracture healing was rarely reported. This study, using the FPR1 knockout (KO) mouse, is one of the first studies that try to investigate FPR1 function to osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in vitro and bone fracture healing in vivo. MATERIALS AND METHODS: Primary BMSCs were isolated from both FPR1 KO and wild type (WT) mice. Cloned mouse BMSCs (D1 cells) were used to examine role of FoxO1 in FPR1 regulation of osteogenesis. A closed, transverse fracture at the femoral midshaft was created to compare bone healing between KO and WT mice. Biomechanical and structural properties of femur were compared between healthy WT and KO mice. KEY FINDINGS: FPR1 expression increased significantly during osteogenesis of both primary and cloned BMSCs. Compared to BMSCs from FPR1 KO mice, WT BMSCs displayed considerably higher levels of osteogenic markers as well as mineralization. Osteogenesis by D1 cells was inhibited by either an FPR1 antagonist cFLFLF or a specific inhibitor of FoxO1, AS1842856. In addition, the femur from WT mice had better biomechanical properties than FPR1 KO mice. Furthermore, bone healing in WT mice was remarkably improved compared to FPR1 KO mice analyzed by X-ray and micro-CT. SIGNIFICANCE: These findings indicated that FPR1 played a vital role in osteogenic differentiation and regenerative capacity of fractured bone, probably through the activation of FoxO1 related signaling pathways.

Role of Formyl Peptide Receptors and ß-Arrestin-1 in suPAR Signal Transduction in Mouse Podocytes: Interactions with αVß3-Integrin.

The soluble urokinase plasminogen activator receptor (suPAR) has been implicated in a wide range of pathological conditions including primary nephrotic syndromes and acute kidney injuries. suPAR can trigger transduction cascades in podocytes by outside-in activation of αVß3-integrin, but there is evidence that the functional cell surface response element is actually a complex of different types of receptors, which may also include the receptor for advanced glycation end-products (RAGE) and formyl peptide receptors (FPRs). Here we observed that ROS accumulation and Src activation could be evoked by continuous 24 h exposure to either suPAR or the FPR agonist fMLF. Responses to suPAR and fMLF were completely blocked by either the FPR antagonist WRW4 or by the αV-integrin inhibitor cilengitide. Moreover, endogenous podocyte mouse Fpr1 co-immunoprecipitates with ß3-integrin, suggesting that these receptors occur as a complex on the cell surface. suPAR- and fMLF-evoked activation of Src and ROS differed in time course. Thus, robust pertussis toxin (PTX)-sensitive responses were evoked by 60 min exposures to fMLF but not to suPAR. By contrast, responses to 24 h exposures to either suPAR or fMLF were PTX-resistant and were instead abolished by knockdown of ß-arrestin-1 (BAR1). FPRs, integrins, and RAGE (along with various Toll-like receptors) can all function as pattern-recognition receptors that respond to "danger signals" associated with infections and tissue injury. The fact that podocytes express such a wide array of pattern-recognition receptors suggests that the glomerular filter is designed to change its function under certain conditions, possibly to facilitate clearance of toxic macromolecules.

Formyl peptide receptors are involved in CTX-induced impairment of lymphocyte functions.

Crotoxin (CTX) is a neurotoxin that is isolated from the venom of Crotalus durissus terrificus, which displays immunomodulatory, anti-inflammatory, and anti-tumoral effects. Previous research has demonstrated that CTX promotes the adherence of leukocytes to the endothelial cells in blood microcirculation and the high endothelial venules of lymph nodes, which reduces the number of blood cells and lymphocytes. Studies have also shown that these effects are mediated by lipoxygenase-derived mediators. However, the exact lipoxygenase-derived eicosanoid involved in the CTX effect on lymphocytes is yet to be characterized. As CTX stimulates lipoxin-derived mediators from macrophages and lymphocyte effector functions could be modulated by activating formyl peptide receptors, we aimed to investigate whether these receptors were involved in CTX-induced redistribution and functions of lymphocytes in rats. We used male Wistar rats treated with CTX to demonstrate that Boc2 (butoxycarbonyl-Phe-Leu-Phe-Leu-Phe), an antagonist of formyl peptide receptors, prevented CTX-induced decrease in the number of circulating lymphocytes and increased the expression of the lymphocyte adhesion molecule LFA1. CTX reduced the T and B lymphocyte functions, such as lymphocyte proliferation in response to the mitogen Concanavalin A and antibody production in response to BSA immunization, respectively, which was prevented by the administration of Boc2. Importantly, mesenteric lymph node lymphocytes from CTX-treated rats showed an increased release of 15-epi-LXA4. These results indicate that formyl peptide receptors mediate CTX-induced redistribution of lymphocytes and that 15-epi-LXA4 is a key mediator of the immunosuppressive effects of CTX.