International Immunopharmacology
Volume 11, booklet 1,
January 2011
, side 55-66
Author links open the overlay panel, , , ,
Abstract
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 CD25−or 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.
introduction
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
discussion
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.
so
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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Cited by (45)
Insights into the role of the resolvin D2-GPR18 signaling axis in cardiovascular physiology and disease
2023, Advances in Pharmacology
Nonzero inflammation is a cause of cardiovascular disease, including atherosclerosis. The resolution of inflammation is an active and highly coordinated process involving the formation of specialized pro-resolution mediators (SPMs) and other factors such as proteins, gases and nucleotides. SPMs comprise a superfamily of lipid mediators that include lipoxins, resolvins, maresins, and protectins. SPMs act through various G protein-coupled receptors (GPCRs) and have been extensively studied in animal models of cardiovascular disease. An emerging literature suggests that SPMs play a protective role in atherosclerosis, as shown using specific SPMs as well as mice lacking their receptors. This review highlights a relatively new pro-resolution signaling axis, namely resolvin D2-GPR18, and how understanding detailed mechanisms and cellular specificity of this signaling axis can help support the development of more targeted pro-resolution therapies for atherosclerosis and associated cardiovascular pathologies .
Specialized pro-resolution mediators as modulators of immune responses
2022, Seminars in immunology
Quote excerpt:
RvE1 can interact with the receptor to block chemerin and LTB4 binding [101]. Similarly, activated CD4 T cells and memory CD4 T cells express high levels of ALX/FPR2, a receptor for both the proinflammatory cytokine serum amyloid A [ 104 ] and RvD1 [ 71 ]. [71]. These apparently opposing actions of SPM receptors illustrate an important concept in solution biology, namely that the actions of the receptors can be ligand- and situation-specific.
Specialized pro-resolving mediators (SPMs) are endogenous small molecules produced primarily from dietary omega-3 polyunsaturated fatty acids by both structural, active, and innate immune cells. Specific pro-resolution mediators have been shown to both limit acute inflammation and promote resolution and return to homeostasis after infection or injury. There is growing evidence that chronic immune disorders are characterized by poor resolution, and SPMs have significant potential as novel therapeutic agents to prevent and treat chronic inflammation and immune system disorders. This review focuses on important breakthroughs in the understanding of how SPMs are produced by and act on cells of the adaptive immune system, specifically macrophages, B cells and T cells. We also highlight recent findings demonstrating the potential of SPMs as novel therapeutics in topics such as immunization, autoimmune diseases, and transplantation.
Functional role of annexins in zebrafish caudal fin regeneration - A gene knockdown approach in tissue regeneration
2020, Biochemistry
Regeneration is an adaptive phenomenon with far-reaching biological effects that affect almost the entire organism, including humans, in a heterogeneous manner. The ability to regenerate varies from species to species due to its complexity Epimorphic regeneration of zebrafish caudal fin tissue is the most studied regeneration mechanism due to its discrete and rapid regenerative ability. Several genes and proteins have been shown to be associated with the regeneration mechanisms of zebrafish caudal fin tissue. In this study, we investigated the functional role of annexin 2a and 2b genes in zebrafish caudal fin tissue regeneration using innovative electroporation techniques to target the gene using CRISPR-Cas9 technology. CRISPR electroporation was performed on caudal fin tissue of adult zebrafish after amputation. We report delayed growth during caudal fin tissue regeneration when annexin 2a and 2b genes were knocked out, which was validated by gene expression and sequencing analysis and further supported by high-throughput quantitative proteomic analysis of fin tissue. Annexin family genes such asANXA13,ANXA1a,ANXA5bIt was also noted that they were suppressed with their expression. shut downANXA2aAnd2bin the regeneration of caudal tissue impairs the ability to regenerate, as these genes are involved in cell-cell communication and extracellular matrix growth. This study proves itANXA2aAnd2bplays an important role in the epimorphic regeneration of caudal fin tissue in zebrafish.
Activation of the formyl peptide receptor inhibits the expansion of effector T cells and synovial fibroblasts and ameliorates joint damage in models of rheumatoid arthritis
2018, International Immunopharmacology
Quote excerpt:
In these studies, Cpd43 may mediate its effects on arthritogenic T cells through different mechanisms. First, since CD4 cells express FPR2 but not FPR1 [7–9] , Cpd43 likely has a direct effect on effector and regulatory T cells via FPR2. Indeed, our results showing reversal of Cpd43-mediated effects on T cells by FPR2 inhibitors confirm that Cpd43 suppresses arthritogenic T-cell immunity in an FPR2-dependent manner.
The effects of formyl peptide receptors (FPRs) on effector T cells and inflammatory tissue cells are not well understood. Here, we investigated the effect of FPR activation on efferent T-cell responses in models of rheumatoid arthritis (RA) and on fibroblast-like synoviocyte (FLS) expansion. Compound 43 (Cpd43; FPR1/2 agonist) was administered to mice with post-onset collagen-induced arthritis (CIA) or antigen-induced arthritis (AIA). Joint inflammation/injury and immunity were assessed. FLS were cultured with Cpd43 to test its effects on cell apoptosis and proliferation. To study the effects of endogenous FPR2 ligands on FLS proliferation, FLS FPR2 was blocked or silenced the expression of Annexin A1 (AnxA1). Cpd43 reduced arthritis severity in both models. In CIA, Cpd43 reduced CD4 T cell proliferation and survival and increased production of the protective cytokine IFNγ in the lymph nodes. In AIA, Cpd43 increased CD4 apoptosis and the production of the anti-inflammatory IL-4, while increasing the proportion of regulatory splenic T cells and their expression of IL-2Rα. In both models, Cpd43 increased CD4-IL-17A production without affecting humoral immunity. FPR2 inhibitors reversed the Cpd43-mediated effects on AIA and T-cell immunity. Cpd43 reduced TNF-induced FLS proliferation and increased FLS apoptosis associated with intracellular FPR2 accumulation, while endogenous AnxA1 and FPR2 reduced FLS proliferation via the ERK and NFκB pathways. Overall, FPR activation inhibits the expansion of arthritogenic effector CD4 T cells and FLS and reduces joint damage in experimental arthritis. This suggests the therapeutic potential of FPR ligation for the treatment of RA.
The intracellular formyl peptide receptor regulates the migration of naïve CD4 T cells
2018, Biochemical and biophysical research communication
We found that formyl peptide receptor (FPR) 1 and FPR3 were expressed intracellularly and/or in the nucleus of naïve CD4 T cells. Activation of naïve CD4 T cells with the synthetic intracellular agonists dTAT-WKYMVm and CTP-WKYMVm for FPR members stimulated CD4 T cell migration via a pertussis toxin-sensitive manner. FPR1 knockdown, but not FPR3 knockdown, blocked dTAT-WKYMVm-induced naïve CD4 T cell migration. Stimulation of naïve CD4 T cells with dTAT-WKYMVm induced activation of ERK, p38MAPK and Akt. Activation of CD4 T cells with anti-CD3 and anti-CD28 antibodies caused surface expression of FPR1 and FPR3, but not FPR2. CD4 T cells isolated from patients with sepsis expressed the three members of the FPR family on their cell surface. Taken together, our results suggest that intracellular FPRs in naïve CD4 T cells and surface FPRs in activated CD4 T cells could regulate immune responses by regulating CD4 T cell activity.
Proteomics-based analysis of lung injury-induced proteins in a mouse model of common bile duct ligation
2017, Chirurgie (USA)
Quote excerpt:
Further immunohistochemical analysis of the lungs revealed that ANXA1-positive cells were dramatically increased in neutrophil and monocyte populations. ANXA1 is a member of the annexin superfamily of calcium-binding proteins and is mainly expressed in neutrophils, eosinophils and monocytes.25-28 Several studies have shown that this protein is involved in leukocyte adhesion and migration during the development of the inflammatory response.
Lung damage is a life-threatening complication in patients with reduced liver function. We have recently provided an experimental lung injury model in mice with common bile duct ligation. In this study, we aimed to characterize the pathological and biochemical features of lung tissue in mice with common bile duct ligation using a proteomic approach.
The common bile ducts of 8-week-old BALB/c mice were surgically ligated. CD31-expressing lung cells were sorted with immunomagnetic microbeads, and protein profiles were examined by two-dimensional gel electrophoresis. Based on the protein identification results, immunohistochemistry and quantitative reverse transcription polymerase chain reaction were performed in lung and liver tissues.
Two-dimensional gel electrophoresis revealed three important inflammation-associated proteins that showed a significant increase in the number of CD31-positive lung cells after common bile duct ligation. Mass spectrometric analysis identified these proteins as SerpinB1a (48 kDa), ANXA1 (46 kDa) and S100A9 (16 kDa). Furthermore, the three proteins were more highly expressed in dilated pulmonary blood vessels of bile duct ligated mice, where neutrophils and monocytes were prominent, as shown by immunohistochemistry. More importantly, SerpinB1a mRNA and protein were significantly upregulated in liver, whereas S100A9 and ANXA1 mRNA and protein were upregulated in lung, as shown by quantitative reverse transcription polymerase chain reaction and Western blot.
Using a proteomics-based approach, we identified three proteins that were highly expressed in the lung after common bile duct ligation.
Selected articles (6)
Research Article
Five-year changes in cardiac structure and function in patients with rheumatoid arthritis compared with the general population
International Journal of Cardiology, Band 240, 2017, S. 379–385
Patients with rheumatoid arthritis (RA) have an increased risk of heart failure if the ejection fraction is preserved. The development and progression of left ventricular dysfunction before the onset of clinical heart failure is unknown. The aim of this study was to evaluate longitudinal changes in cardiac structure and function in patients with RA compared with individuals in the general population.
A prospective, longitudinal study of a population-based cohort of 160 patients with RA and a population-based cohort of 1391 individuals without RA (non-RA cohort). Each participant underwent two-dimensional pulsed wave tissue Doppler echocardiography at baseline and at 4 to 5 years of follow-up. Age- and sex-adjusted linear regression models were used to test for differences between RA and non-RA cohorts in annual changes for echocardiographic parameters.
Mitral A velocity increased faster in patients with RA than in the non-RA cohort (age- and sex-adjusted parameter estimate 0.030;P<0.001). Accordingly, the mean E/A ratio of mitral inflow decreased faster in the RA cohort than in the non-RA cohort (adjusted parameter estimate: −0.096;P<0.001). The left atrial volume index increased more in the RA cohort than in the non-RA cohort (adjusted parameter estimate 0.150;P<0.001).
This pattern of echocardiographic findings confirms previous cross-sectional studies and suggests that subclinical changes in diastolic function occur more rapidly in RA patients than in the general population over a 5-year period. Further investigation of the mechanisms of myocardial disease in these patients and its association with disease activity and treatment is needed.
Research Article
Estrogen and immune modulation: novel mechanisms affecting peripheral and central immunity
Current Opinion in Pharmacology, Band 13, Ausgabe 4, 2013, S. 576-581
The regulation of the immune response to infection or tissue damage is a complex interaction between several factors. However, it has long been known that steroid hormones can exert potent modulatory effects at all levels of the innate and adaptive immune system. Although glucocorticoids receive most of the attention due to their widespread clinical use, it is becoming increasingly clear that sex steroid hormones, and especially the major female sex steroid, estrogen, have powerful effects on immune responses. In this review, we discuss recent evidence for estrogen's effects on various cellular components of the immune system and how this hormone may offer new opportunities to pharmacologically exploit the immune response.
Research Article
Examining the functional selectivity of β-adrenergic receptors reveals novel signaling modes and potential therapeutic applications
Catecholamine Research in the 21st Century, 2014, p 112
Research Article
The lack of TNFRI signaling increases the biological activity of annexin A1 in intestinal inflammation
Biochemical Pharmacology, bind 98, udgave 3, 2015, s. 422-431
We investigated whether the absence of TNF-α signaling increases mucosal levels of annexin A1 (AnxA1); The hypothesis is based on previous findings showing that neutralization of TNF-α in patients with Crohn's disease upregulates systemic AnxA1 expression. Biopsies from healthy volunteers and patients on anti-TNF-α therapy with remitting ulcerative colitis (UC) showed higher AnxA1 expression than those with active disease. We also investigated acute dextran sulfate sodium (DSS) colitis in the TNF-α receptor 1 KO strain (TNFR1-/-) with impaired TNF-α signaling and in C57BL/6 mice (WT). Although both strains developed colitis, TNFR1-/- mice showed early clinical recovery, lower myeloperoxidase (MPO) activity and milder histopathological changes. The colonic epithelium of control and DSS-treated TNFR1−/− mice showed intense AnxA1 expression, and AnxA1+ CD4+ and CD8+ T cells were more frequent in TNFR1−/− animals, indicating an additional supply of AnxA1. The pan antagonist of AnxA1 receptors exacerbated colitis outcomes in TNFR1−/− mice, supporting the crucial role of AnxA1 in early recovery. Our results demonstrate that reduction of TNF-α signaling favors the expression and biological activity of AnxA1 in inflamed intestinal mucosa.
Research Article
ANXA1 released from intestinal epithelial cells ameliorates DSS-induced colitis by increasing NKG2A expression by natural killer cells
Biochemical and Biophysical Research Communications, Band 478, Ausgabe 1, 2016, S. 213–220
Inflammatory bowel disease (IBD) occurs when intestinal immune homeostasis is disrupted. The maintenance of this homeostasis is mainly controlled by the interaction between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). IECs can prevent contact between luminal bacteria and immune cells by forming a physical barrier and expressing antimicrobial peptides to maintain intestinal immune homeostasis. During colitis, the IECs can express increased levels of ANXA1, which is important for the regeneration of the intestinal mucosa and functions as a potent anti-inflammatory protein. Natural killer (NK) cells can also suppress the development of colitis. The impact of the interaction between injured IECs and recruited NK cells during colitis is uncertain. In this study, expression of ANXA1 was increased in IECS from DSS-treated mice, and more NK cells were recruited to the intestinal mucosa. Furthermore, the expression of NKG2A was upregulated when co-cultured with NK cells. The results also showed that overexpression of NKG2A in NK cells is important for inhibition of neutrophil recruitment and activity to alleviate DSS-induced colitis. Here, we present a novel anti-inflammatory mechanism via ANXA1 secreted by injured IECs, whereby ANXA1 can stimulate the expression of NKG2A in NK cells, affecting neutrophil recruitment and activity, which are necessary for the pathology of colitis.
Research Article
Cardioprotective potential of annexin A1 mimics in myocardial infarction
Pharmacology & Therapeutics, Band 148, 2015, S. 47-65
Myocardial infarction (MI) and the resulting heart failure remain one of the leading causes of death worldwide. Current treatments for patients with MI are revascularization with thrombolytics or interventional procedures. The focus of these treatments was to restore perfusion to ischemic tissue to prevent tissue necrosis and preserve organ function. However, restoration of blood flow after a period of ischemia can lead to further myocardial damage, known as reperfusion injury. Pharmacological interventions such as antioxidants and Ca2+Channel blockers have demonstrated premises in experimental settings; However, clinical trials have shown only limited success. Therefore, there is a need to develop new therapies for the treatment of reperfusion injury. The therapeutic potential of the glucocorticoid-regulated anti-inflammatory mediator annexin-A1 (ANX-A1) has recently been recognized in a number of systemic inflammatory diseases. ANX-A1 binds to and activates the formyl peptide receptor family (G protein-coupled receptor family) to inhibit neutrophil activation, migration and infiltration. Until recently, studies on the cardioprotective effects of ANX-A1 and its peptidomimetics (Ac2-26, CGEN-855A) have mainly focused on its anti-inflammatory effects as a mechanism to preserve myocardial viability after I-R injury. Our laboratory provided the first evidence of the direct protective effect of ANX-A1 on the myocardium, independent of inflammatory cells in vitro. We are now investigating the potential of ANX-A1-based therapies as a “triple shield” therapy against myocardial IR injury that limits neutrophil infiltration and preserves both cardiomyocyte viability and contractile function. This new therapy could therefore represent a valuable clinical approach to improve outcome after myocardial infarction.
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