Comparative analysis of annexin A1 formyl peptide receptor 2/ALX expression in human leukocyte subsets (2023)

International Immunopharmacology

Volume 11, booklet 1,

January 2011

, side 55-66

Author links open the overlay panel, , , ,


Recent studies have linked abnormal expression of the annexin A1/formyl peptide receptor 2 (FPR2/ALX) system to the development of autoimmune diseases. In this study, we systematically screened subsets of human leukocytes for the presence of this signaling pathway to provide a roadmap that will help researchers explore possible links between the development of immune-related disorders and the expression of this system. Our results show itNeutrophils,monocytesand NK cells express higher levels of AnxA1 and FPR2/ALX compared to T or B cells. Further analysis more specificT-cell subsetsgave higher values ​​when activatedCD25+and memory CD45ROCD4 T-cellercompared to the rest CD25or naive's CD45RA CD4T-celler. Together, the results expand our knowledge of the AnxA1-FPR2/ALX systemimmune cellsand provide new opportunities to study their functionssignalwayin systems other than that, where classically described for neutrophils.

Research highlights

►This is the first study to show FPR2/ALX as a true receptor for full-length annexin-A1. ►This study showed that Annexin-A1 modulates the strength of TCR signaling. ►A comprehensive overview of the biological functions of formyl peptide receptors. ►This study provided the first evidence for Annexin A1-derived peptides as ligands for formyl peptide receptors.


Evidence accumulated over the past five years has shown that AnxA1 is a novel endogenous homeostatic mediator of the immune system with unique, non-redundant functions that vary depending on the cell type and cell location in which it is expressed [1] , [2] . In the innate immune cells, AnxA1 is expressed at very high levels and stored in specific cytoplasmic and membrane compartments, where it plays distinct but complementary roles in the initial phase of the inflammatory response [3], [4]. For example, the rapid release of AnxA1 from the gelatinase granules [5] of activated neutrophils [6] plays an important role in combating adhesion to inflamed microvascular wallsoverL-selectin cleavage [7] and through binding of its cognate receptor FPR2/ALX [8], [9]. In the same cells, AnxA1 is also released into the extracellular environmentoverspecialized cellular “packages” called microparticles that adhere to activated HUVEC [10]. Conversely, AnxA1 bound to the membrane of neutrophils acts as a phagocytic signal for activated macrophages [11], and its absence in the latter leads to a significant impairment of their phagocytic activity [12], [13]. Similar,Mycobacterium tuberculosis-Infected macrophages release AnxA1 on the cell membrane to form an apoptotic sheath, a special structure that triggers “altruistic suicide” of these cells, ultimately leading to host protection [14].

Using human recombinant AnxA1 and its peptidomimetics as pharmacological tools, we have shown that this protein can inhibit neutrophil recruitment in several casesDirectModels of acute inflammation [15], [16], [17], [18]. Accordingly, the absence of AnxA1 in cells of the innate immune system leads to an increased inflammatory response. AnxA1-deficient mice showed an increased and/or prolonged inflammatory response in acute inflammatory models such as paw edema and zymosan peritonitis [4] , [19] . Characterization of AnxA1-deficient neutrophils further showed a higher susceptibility to activation [19] and to transition to diapedesis via cremaster venules in response to platelet-activating factor superfusion [20].

Studies of adaptive immune cells have shown a completely different picture[21], [22]. In T cells, AnxA1 is mainly, if not exclusively, expressed in the cytosolic compartment. However, suggestionsoverThe TCR leads to the release of AnxA1 into the extracellular space and concomitant externalization of the receptor FPR2/ALX on the cell surface [23]. The functional aspect of this event is to provide an additional signaling pathway that integrates with the TCR machinery to help regulate T cell activation. Accordingly, activation of T cells in the presence of exogenous recombinant AnxA1 lowers the activation threshold and leads to hyperproliferation of T cells [23], while genetic ablation of AnxA1 in T cells results in an impaired response to TCR stimulation [24] .

FPR2/ALX is a member of the G-coupled FPR receptor family, which in humans includes two other members: FPR1 and FPR3 [ 25 ]. These receptors recognize a variety of structurally unrelated natural and synthetic ligands, including aryl carboxylic acid hydrazide AG-14, cheno/deoxycholic acid CDCA/DCA, aspirin-triggered lipoxin (ALX), the peptides LL-37 and CCL23β, and serum amyloid A (SAA) and the eponymous agonist peptide fMLP [26], [27], [28]. Pioneering studies by Walter et al. and other studies have identified the N-terminal derived AnxA1 peptide Ac.2–26 as a ligand for FPR1 [29] , [30] , [31] . Further studies extended these observations and showed that FPR2/ALX is the true receptor for the full-length protein [8] , [9] . Consistent with these results, full-length recombinant AnxA1 in Fpr1 showed only a partial loss of its anti-inflammatory activity−/−Mouse [15], while these appeared to be ablated in Fpr2−/−animals [32].

Taken together, these observations suggest that dysregulated expression of this pathway, whether enhanced or suppressed, can significantly affect the response of both the innate and adaptive parts of the immune system during the development of inflammatory and autoimmune diseases. In this study, we performed a systematic analysis and comparison of the expression of the AnxA1-FPR2/ALX system in different subsets of human peripheral leukocytes to provide a reference system for these studies. These findings expand our current knowledge of AnxA1-FPR2/ALX signaling and may spur further investigations into the biological functions of this signaling pathway in a number of previously neglected immune cell types known to play key roles in inflammatory and autoimmune diseases.

sectional cuts

Antibodies and reagents

To characterize the different leukocyte subsets, flow cytometry was performed with either fluorescein isothiocyanate (FITC), phycoerythrin (PE) or PerCP-Cy5.5-conjugated monoclonal antibodies: anti-CD3 (clone UCHT), anti-CD4 (clone). RPA-T4), anti-CD8 (clone RPA-T8), anti-CD14 (clone 61D3), anti-CD19 (clone HIB19), anti-CD25 (clone BC96), anti-CD45RA (HI100) and anti-CD45RO ( UCHL1) and anti-CD335 (NKp46). The monoclonal anti-AnxA1 antibody has been previously described [33], while the monoclonal

AnxA1 expression throughout the PMN and PBMC populations

PMN and PBMC populations were separated from peripheral blood of healthy volunteers using a standard double-density purification protocol, and AnxA1 levels in total cell lysates obtained from equal numbers of PMN and PBMC were compared by Western blot. AnxA1 expression was readily detectable as early as 7.5 × 103PMN, while using an equal number of PBMC, a weak band could be seen (Fig. 1A, first and third panels from the top, respectively). A linear correlation between AnxA1


A growing body of evidence points to a link between AnxA1 levels and the occurrence of inflammatory and immune-related diseases. Interestingly, however, there are several apparent contradictions in the literature in this regard, depending on the experimental approach or sample used to measure expression levels of AnxA1. For example, in cystic fibrosis (cystic fibrosis), a chronic, life-shortening genetic disease that is characterized by lung, pancreatic and intestinal diseases and has a chronic course

Disclosure of conflicts of interest

The authors have no conflict of interest to disclose.


LS was supported by a Wolfson grant. MP-R and SN were supported byBritish Heart Foundation UK(GrantsPG/06/153/22042AndPG/09/060). We would like to thank Diane Cooper for helpful suggestions and for carefully reading the manuscript.


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