scholarly journals M6PR-Specific Targeting of Lysosomal Heparanase Regulates Platelet Hemostatic Function in Mice

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1059-1059
Author(s):  
Nathan Eaton ◽  
Caleb Drew ◽  
Theresa A. Dlugi ◽  
Karin M. Hoffmeister ◽  
Hervé Falet
Keyword(s):  
Platelet Function ◽  
Conflicts Of Interest ◽  
Blood Platelets ◽  
Critical Role ◽  
Fluorescent Microscopy ◽  
Type I ◽  
Dense Granules ◽  
Specific Targeting

Besides α-granules and dense granules, which play critical roles in and beyond hemostasis, circulating blood platelets and their precursor cells megakaryocytes contain lysosomes, the contents of which are also secreted during platelet activation. In their delivery to the lysosome, acid hydrolases bearing phosphomannosyl residues are trafficked from the trans-Golgi network to the acidic late-endosomal compartment via the mannose 6-phosphate receptor (M6PR) pathway. To determine the role of M6PR-specific targeting of lysosomal enzymes in platelet function, platelet parameters were investigated in M6pr-/- mice lacking the 46-kDa M6PR, the physiological role of which is unclear. M6pr-/- mice had normal platelet count but displayed an increased number of distinct proplatelet-like cells compared to control mice, as determined by immunofluorescent microscopy. Moreover, transmission electron microscopy revealed the presence of abnormal membrane tubulations, elongated and electron-dense granules, and large vacuole-like structures within resting M6pr-/- platelets. M6pr-/- platelets expressed normally major glycoproteins on their surface and von Willebrand factor and fibrinogen in their α-granules. M6pr-/- mice were hyper-thrombotic, as assessed by tail bleeding time, and M6pr-/- platelets adhered to type I collagen with a significantly greater propensity than control platelets under arterial shear in in vitro flow experiments. Heparanase, an endo-β-glucuronidase that cleaves extracellular matrix heparan sulfate proteoglycans, is the most abundant lysosomal enzyme in platelets. Thus, its contribution to the phenotype of M6pr-/- mice was investigated further. Heparanase expression was decreased in the bone marrow megakaryocytes and blood platelets of M6pr-/- mice and increased in M6pr-/- plasma, as evidenced by immunoblot and fluorescent microscopy analysis, consistent with its mistargeting in the absence of M6PR. Interestingly, pharmacological inhibition of heparanase with OGT 2115 normalized the adhesion of M6pr-/- platelets to collagen in vitro, indicating that increased plasma heparanase contributes to the thrombotic phenotype of M6pr-/- mice. Taken together, the data suggest that the M6PR-specific targeting of lysosomal heparanase plays a critical role in platelet function, thereby regulating hemostasis. Disclosures No relevant conflicts of interest to declare.

A Critical Role of Mir-9 in Myelopoesis and EVI1-Induced Leukemogenesis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2332-2332
Author(s):  
Vitalyi Senyuk ◽  
Yunyuan Zhang ◽  
Yang Liu ◽  
Ming Ming ◽  
Jianjun Chen ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Ectopic Expression ◽  
Myeloid Differentiation ◽  
Dna Hypermethylation ◽  
Hematopoietic Stem

Abstract Abstract 2332 MicroRNA-9 (miR-9) is required for normal neurogenesis and organ development. The expression of miR-9 is altered in several types of solid tumors suggesting that it may have a function in cell transformation. However the role of this miR in normal hematopoiesis and leukemogenesis is unknown. Here we show that miR-9 is expressed at low levels in hematopoietic stem/progenitor cells (HSCs/HPCs), and that it is upregulated during hematopoietic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelopoiesis, while promoting apoptosis in vitro and in vivo. In addition, the inhibition of miR-9 in HPC with a miRNA sponge blocks myelopoiesis. EVI1, required for normal embryogenesis, and is considered an oncogene because inappropriate upregulation induces malignant transformation in solid and hematopoietic cancers. In vitro, EVI1 severely affects myeloid differentiation. Here we show that EVI1 binds to the promoter of miR-9–3 leading to DNA hypermethylation of the promoter as well as repression of miR-9. We also show that ectopic miR-9 reverses the myeloid differentiation block that is induced by EVI1. Our findings suggest that inappropriately expressed EVI1 delays or blocks myeloid differentiation, at least in part by DNA hypermethylation and downregulation of miR-9. It was previously reported that FoxOs genes inhibit myeloid differentiation and prevent differentiation of leukemia initiating cells. Here we identify FoxO3 and FoxO1 as new direct targets of miR-9 in hematopoietic cells, and we find that upregulation of FoxO3 in miR-9-positive cells reduces the acceleration of myelopoiesis. These results reveal a novel role of miR-9 in myelopoiesis and in the pathogenesis of EVI1-induced myeloid neoplasms. They also provide new insights on the potential chromatin-modifying role of oncogenes in epigenetic changes in cancer cells. Disclosures: No relevant conflicts of interest to declare.

Mir-29a Displays in Vitro and in Vivo Anti-Tumor Activity in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2090-2090
Author(s):  
Manujendra N Saha ◽  
Yan Chen ◽  
Jahangir Abdi ◽  
Hong Chang
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Treatment Strategies ◽  
Loss Of Function

Abstract Despite advances in recent therapeutic approaches including targeted therapies, multiple myeloma (MM) remains still incurable necessitating the development of novel treatment strategies. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate post-transcriptional gene expression and play a critical role in tumor pathogenesis. Tumor suppressor miRNAs are generally down-regulated in cancer cells compared to their normal counterpart, and their enforced expression indeed represents a promising strategy for cancer treatment. In this study, we sought to characterize the role of miR-29a as a tumor suppressor as well as evaluated its therapeutic potential in MM. miR-29a expression levels were found down-regulated in a panel of 5 MM cell lines, 6 newly diagnosed MM patient samples compared to its expression in normal hematopoietic cells collected from 10 normal healthy individuals suggesting that high expression of miR-29a might be involved in MM pathogenesis. We further assessed the functional significance of miR-29a by both gain- and loss-of-function studies. A significant decrease in cell viability (22-32%, p<0.05), along with induction of apoptosis (30-35%, p<0.05) was observed at 48 hrs in MM cell lines, MM.1S and 8226 transfected with miR-29a compared to cells transfected with scrambled miRNA. In contrast, cell lines transfected with miR-29a antagonist prevented the loss of viability in such cells indicating the specificity of miR-29a. At the molecular level, we have identified c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, as a target of miR-29a. Binding site of miR-29a was first identified by computer algorithm and further confirmed by the use of a 3’UTR of c-Myc reporter (luciferase renilla/firefly) constructs containing, miR-29a target site. Moreover, treatment with PRIMA-Met, a small molecule anti-tumor agent in phase I/II clinical trials, significantly increased the expression of miR-29a (2 to 6-fold) and decreased expression of c-Myc in MM cell lines and primay MM patient samples suggesting an important role of miR-29a in inhibiting proliferation of MM cells. On the other hand, overexpression of c-Myc in 8226 and MM.1S cells at least partially reverted the functional effect of miR-29a or PRIMA-1Metsuggesting a specific role of c-Myc in mediating its anti-proliferative activity. To examine therapeutic potential of our studies, we took advantage of novel lipid based delivery method of miRNA. Intratumor delivery of the miR-29a by intraperitoneal injection route against MM xenografts in SCID mice resulted in a significant inhibition of tumor growth (~60%) at 12 days of treatment and prolongation of survival (median survival increased from 22 days to 35 days, p<0.038) compared to the mice receiving scrambled miRNA. Retrieved tumors from treated mice showed efficient increase in miR-29a (5.5-fold, p=0.025), and decrease in c-Myc protein as well as reduced expression of Ki67 and increase of Tunel expression. Similar phenomenon was observed by systematic delivery of miR-29a (by intraveneous injection) in mice with no significant side effects or toxicity in mice. Our study reveals an important role of miR-29a as a tumor suppressor in mediating anti-tumor activities in MM cells by targeting c-Myc. Our findings provide a proof-of-principle that formulated synthetic miR-29a exerts therapeutic activity in preclinical models, and support a framework for development of miR-29a based treatment strategies in MM patients. Disclosures No relevant conflicts of interest to declare.

Critical Role of CalDAG-GEFI In FCγRIIa-Dependent Platelet Activation and Thrombosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3196-3196
Author(s):  
Moritz Stolla ◽  
Lucia Stefanini ◽  
Timothy Daniel Ouellette ◽  
Firdos Ahmad ◽  
Michael P Reilly ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Nucleotide Exchange ◽  
Pulmonary Thrombosis ◽  
Nucleotide Exchange Factor ◽  
Immune Mediated

Abstract Abstract 3196 Immune-mediated thrombosis is a major cause of death in autoimmune diseases and contributes to complications in drug treatments (e.g. Heparin Induced Thrombocytopenia). The major receptor on platelets for immunoglobulin-mediated activation is FcγRIIA. FcγRIIA signals through an immunoreceptor tyrosine-based activation motif (ITAM) that leads to phospholipase C activation, which induces the release of calcium and diacylglycerol (DAG). In our previous work, we identified CalDAG-GEFI (calcium and DAG regulated guanine nucleotide exchange factor I) as a key component of collagen/ITAM-mediated platelet activation. In the current study, we evaluated if CalDAG-GEFI is a potential target for the intervention with FcγRIIA receptor dependent, immune-mediated thrombosis. Mice transgenic for the human FcγRIIA (hFCR) and deficient for CalDAG-GEFI-/- (hFCR/CDGFI-/-) were generated. In vitro, aggregation of hFCR/CDGFI-/- platelets required 50–100-fold higher concentrations of anti-CD9 antibodies than hFCR/WT controls. In comparison, inhibition of P2Y12, the target of clopidogrel, shifted the dose response curve for anti-CD9 in hFCR/WT platelets by only ∼2-fold. In addition to their aggregation defect, hFCR/CDGFI-/- platelets were characterized by markedly impaired Rap1 activation. To assess the role of CalDAG-GEFI in FcγRIIA -mediated thrombosis in vivo, we developed a model of antibody-mediated thrombosis, were we injected mice with an Alexa-750 labeled antibody against GPIX and extracted the lungs to visualize pulmonary thrombosis on a LICOR scanner. Anti-GPIX induced pulmonary thrombosis in hFCR mice but not in WT animals. Pretreatment with clopidogrel did not provide a substantial protection from thrombosis in hFCR mice. In contrast, no pulmonary thrombi were observed in hFCR/CDGFI-/- mice. Together, our studies are the first to highlight the importance of CalDAG-GEFI downstream of platelet Fc-receptor/ITAM signaling and suggest CalDAG-GEFI as a powerful new target in the intervention of immune-mediated thrombosis. Disclosures: No relevant conflicts of interest to declare.

CD169+ Macrophages Regulate Erythropoiesis Under Homeostasis, Recovery From Erythron Injury and in JAK2V617F-Induced Polycythemia Vera

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 80-80
Author(s):  
Andrew Chow ◽  
Matthew Huggins ◽  
Jalal Ahmed ◽  
Daniel Lucas ◽  
Daigo Hashimoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Iron Chelation ◽  
Mononuclear Phagocytes ◽  
Novel Strategy

Abstract Abstract 80 The role of macrophages (MΦ) in erythropoiesis was suggested several decades ago with the description of “erythroblastic islands” in the bone marrow (BM) composed of a central MΦ surrounded by developing erythroblasts. This hypothesis was strengthened by in vitro observations using cell culture systems showing that MΦ promote erythroblast proliferation and survival. However, the in vivo role of MΦ in erythropoiesis under homeostasis or disease remains unclear. Central MΦ reportedly express CD169 (or Sialoadhesin), an antigen that specifically marks tissue resident MΦ among mononuclear phagocytes of the bone marrow and spleen. Specific depletion of CD169+ MΦ markedly reduced erythroblasts in the BM (40.4+1.8%) but did not result in overt anemia under homeostasis, likely due to concomitant compensatory splenic erythropoiesis and alterations in RBC clearance. However, MΦ depletion significantly impaired erythroid recovery from PHZ-induced hemolytic anemia (reticulocytes: 8.2-fold lower, p<0.01 and hematocrit: 2-fold lower, p<0.01 on day 6 post-PHZ challenge) and acute blood loss (reticulocytes: 3.2-fold lower, p<0.001 and hematocrit: 1.6-fold lower, p<0.001 on day 4 post-phlebotomy). Furthermore, depletion of CD169+ MΦ in the BM and spleen impaired erythroblast recovery seven days after bone marrow transplantation (BM: 8.2-fold lower, p<0.01 and spleen: 120-fold lower, p<0.05 on day 7 post-BMT) and delayed recovery of reticulocyte numbers (4-fold lower, p<0.001 on day 10 post-BMT) and hematocrit (1.1-fold lower, p<0.05 on day 14 post-BMT). Mechanistically, we observed a rapid drop in reticulocyte hemoglobin content (CHr) in CD169+ MΦ-depleted animals starting four days post-BMT, but iron supplementation was unable to correct the impaired expansion of erythroblasts, suggesting other mechanisms. We determined that VCAM-1 expressed by BM CD169+ MΦ and BMP4 derived from splenic red pulp macrophages were critical for the efficient recovery of the erythron after BMT. Moreover, depletion of host-derived, radioresistant macrophages shortly after transplantation was sufficient to delay erythroblast recovery, implicating a critical role for this population until donor-derived macrophages can repopulate post-BMT. In addition, we characterized a CD169+ VCAM1+ MΦ population in human BM aspirates that represents the first step in clinically targeting the analogous BM resident macrophage population in humans. Since CD169+ MΦ support recovery after erythropoietic injury, we hypothesized that MΦ depletion could potentially normalize the erythron in a JAK2V617F-driven murine model of polycythemia vera (PV). Indeed, we observed that MΦ depletion in PV mice reduced erythroblasts in the BM (1.6-fold lower, p<0.05 after 4 weeks of depletion) and spleen (14-fold lower, p<0.01 after 4 weeks of depletion). This reduction of the expanded PV erythron was associated with an efficient (within 20 days of MΦ depletion) and durable (up to 40 days after last depletion) normalization of the hematocrit. A rapid and durable reduction in CHr was observed after MΦ depletion in PV mice, but systemic iron chelation did not produce the same effect as MΦ depletion, further confirming the contribution of additional mechanisms. MΦ depletion abrogated the induction of BMP4 (3.4-fold lower, p<0.001) and stress erythropoiesis (stress BFU-E: 790-fold reduction, p<0.05) in the spleen. Importantly, MΦ depletion reduced the number of erythropoietin-independent colonies in the spleen of PV mice (endogenous BFU-E: 29-fold lower, p<0.05 and endogenous CFU-E: 1400-fold lower, p<0.05), indicating that erythropoiesis in PV, unexpectedly, remains under the control of MΦ in the BM and splenic microenvironments. Altogether, these studies strongly support the notion that CD169+ MΦ promote erythrocyte development and that modulation of the MΦ compartment represents a novel strategy to treat erythropoietic disorders. Disclosures: No relevant conflicts of interest to declare.

Phosphoinositide 3-kinases and the regulation of platelet function

2004 ◽  
Vol 32 (2) ◽  
pp. 387-392 ◽  
Author(s):  
S.P. Jackson ◽  
C.L. Yap ◽  
K.E. Anderson
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Critical Role ◽  
Receptor Activation ◽  
Clear Understanding ◽  
Integrin Αiibβ3 ◽  
Adhesion Receptor ◽  
Input Signals

A clear understanding of the role of PI (phosphoinositide) 3-kinases in supporting the haemostatic function of platelets has been slow to evolve. In fact, insight into the roles of individual PI 3-kinase isoforms in platelet function remains rudimentary. However, based on in vitro studies using wortmannin and LY294002, there is evidence for an important role for PI 3-kinases in regulating a broad range of functional platelet responses, including primary platelet adhesion, cytoskeletal remodelling and platelet aggregation. One of the critical platelet responses involves affinity regulation of the major platelet integrin αIIbβ3, the primary receptor mediating platelet aggregation and thrombus growth. The input signals regulating integrin αIIbβ3 can be divided into three main groups: (1) Gq-coupled receptors linked to the activation of PLCβ (phospholipase Cβ); (2) Gi-coupled receptors linked to the regulation of adenylate cyclase and Rap1b; and (3) adhesion receptor signalling involving Src kinase-dependent activation of PLCγ isoforms. PI 3-kinases have not been demonstrated to play a critical role in Gq-dependent platelet activation; however, one or more PI 3-kinase isoforms appears to be important for Gi-dependent activation of Rap1b and adhesion receptor activation of PLCγ isoforms. Thus distinct co-operative PI 3-kinase signalling mechanisms appear to play an important role in regulating the adhesive function of integrin αIIbβ3.

KAUTILYA ON THE SCOPE AND METHODOLOGY OF ACCOUNTING, ORGANIZATIONAL DESIGN AND THE ROLE OF ETHICS IN ANCIENT INDIA

2004 ◽  
Vol 31 (2) ◽  
pp. 125-148 ◽  
Author(s):  
Balbir S. Sihag
Keyword(s):  
Economic Development ◽  
Economic Performance ◽  
Organizational Design ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Ethical Values ◽  
Allocation Of Resources ◽  
Economic Data ◽  
Ancient India

Kautilya, a 4th century B.C.E. economist, recognized the importance of accounting methods in economic enterprises. He realized that a proper measurement of economic performance was absolutely essential for efficient allocation of resources, which was considered an important source of economic development. He viewed philosophy and political science as separate disciplines but considered accounting an integral part of economics. He specified a very broad scope for accounting and considered explanation and prediction as its proper objectives. Kautilya developed bookkeeping rules to record and classify economic data, emphasized the critical role of independent periodic audits and proposed the establishment of two important but separate offices - the Treasurer and Comptroller-Auditor, to increase accountability, specialization, and above all to reduce the scope for conflicts of interest. He also linked the successful enforcement of rules and regulations to their clarity, consistency and completeness. Kautilya believed that such measures were necessary but not sufficient to eliminate fraudulent accounting. He also emphasized the role of ethics, considering ethical values as the glue which binds society and promotes economic development.

scholarly journals NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2999
Author(s):  
Deborah Reynaud ◽  
Roland Abi Nahed ◽  
Nicolas Lemaitre ◽  
Pierre-Adrien Bolze ◽  
Wael Traboulsi ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Major Gene ◽  
Critical Role ◽  
Orthotopic Model ◽  
Independent Manner ◽  
Maternal Immune Response ◽  
The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

scholarly journals The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Anagha Deshpande ◽  
Khan L. Cox ◽  
Fan Xuan ◽  
Mohamad Zandian ◽  
...  
Keyword(s):  
Critical Role ◽  
Cellular Transformation ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Nucleosome Core ◽  
Stem And Progenitor Cells ◽  
Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

scholarly journals Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

scholarly journals The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4370
Author(s):  
Cássia de Fáveri ◽  
Paula M. Poeta Fermino ◽  
Anna P. Piovezan ◽  
Lia K. Volpato
Keyword(s):  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Integrative Review ◽  
Inflammatory Factors ◽  
Resolvin D1 ◽  
Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

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