{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:55:58Z","timestamp":1790740558156,"version":"4.1.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Familial Mediterranean fever (FMF) is caused by pyrin-encoding <jats:italic>MEFV<\/jats:italic> gene mutations and characterized by the self-limiting periods of intense inflammation, which are mainly mediated by a massive influx of polymorphonuclear neutrophils (PMNs) into the inflamed sites. Perturbation of actin polymerization by different pathogens was shown to activate the pyrin inflammasome. Our aim was to test whether cytoskeletal dynamics in the absence of pathogens may cause abnormal activation of PMNs from FMF patients. We also aimed to characterize immunophenotypes of circulating neutrophils and their functional activity. Circulating PMNs displayed heterogeneity in terms of cell size, granularity and immunophenotypes. Particularly, PMNs from the patients in acute flares (FMF-A) exhibited a characteristic of aged\/activated cells (small cell size and granularity, up-regulated CXCR4), while PMNs form the patients in remission period (FMF-R) displayed mixed fresh\/aged cell characteristics (normal cell size and granularity, up-regulated CD11b, CD49d, CXCR4, and CD62L). The findings may suggest that sterile tissue-infiltrated PMNs undergo reverse migration back to bone marrow and may explain why these PMNs do not cause immune-mediated tissue damage. A multidirectional expression of Fc\u03b3Rs on neutrophils during acute flares was also noteworthy: up-regulation of Fc\u03b3RI and down-regulation of Fc\u03b3RII\/Fc\u03b3RIII. We also observed spontaneous and fMPL-induced activation of PMNs from the patients after transmigration through inserts as seen by the increased expression of CD11b and intracellular expression of IL-1\u03b2. Our study suggests heightened sensitivity of mutated pyrin inflammasome towards cytoskeletal modifications in the absence of pathogens.<\/jats:p>","DOI":"10.3389\/fimmu.2021.672728","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T05:54:52Z","timestamp":1621230892000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Transmigration of Neutrophils From Patients With Familial Mediterranean Fever Causes Increased Cell Activation"],"prefix":"10.3389","volume":"12","author":[{"given":"Anush","family":"Martirosyan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Poghosyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Ghonyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nune","family":"Mkrtchyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayane","family":"Amaryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayane","family":"Manukyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.02.020","article-title":"Gain-of-Function Pyrin Mutations Induce NLRP3 Protein-Independent Interleukin-1\u03b2 Activation and Severe Autoinflammation in Mice","volume":"34","author":"Chae","year":"2011","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.00456","article-title":"Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever","volume":"31","author":"Manukyan","year":"2016","journal-title":"Front Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.3.851","article-title":"The Familial Mediterranean Fever Protein, Pyrin, Associates With Microtubules and Colocalizes With Actin Filaments","volume":"98","author":"Mansfield","year":"2001","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3181\/0806-RM-184","article-title":"Pyrin and ASC Co-Localize to Cellular Sites That are Rich in Polymerizing Actin","volume":"234","author":"Waite","year":"2009","journal-title":"Exp Biol Med (Maywood)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.04.004","article-title":"A Burkholderia Type VI Effector Deamidates Rho GTPases to Activate the Pyrin Inflammasome and Trigger Inflammation","volume":"19","author":"Aubert","year":"2016","journal-title":"Cell Host Microbe"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature13449","article-title":"Innate Immune Sensing of Bacterial Modifications of Rho Gtpases by the Pyrin Inflammasome","volume":"513","author":"Xu","year":"2014","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20142384","article-title":"Aberrant Actin Depolymerization Triggers the Pyrin Inflammasome and Autoinflammatory Disease That is Dependent on IL-18, Not IL-1\u03b2","volume":"212","author":"Kim","year":"2015","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1601700113","article-title":"Site-Specific Phosphorylation and Microtubule Dynamics Control Pyrin Inflammasome Activation","volume":"113","author":"Gao","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B9","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/nature02393","article-title":"Insight Into Tubulin Regulation From a Complex With Colchicine and a Stathmin-Like Domain","volume":"428","author":"Ravelli","year":"2004","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24231","article-title":"The Effect of Colchicine on Pyrin and Pyrin Interacting Proteins","volume":"113","author":"Taskiran","year":"2012","journal-title":"J Cell Biochem"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.10.3223","article-title":"The Gene for Familial Mediterranean Fever, MEFV, is Expressed in Early Leukocyte Development and is Regulated in Response to Inflammatory Mediators","volume":"95","author":"Centola","year":"2000","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1136\/jim-52-01-28","article-title":"Neutrophil Adhesion Molecule Expression in Familial Mediterranean Fever: Discordance Between the Intravascular Regulation of Beta2 Integrin and L-selectin Expression in Acute Attack","volume":"52","author":"Molad","year":"2004","journal-title":"J Investig Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2012.10.007","article-title":"Activated Phenotype of Circulating Neutrophils in Familial Mediterranean Fever","volume":"218","author":"Manukyan","year":"2013","journal-title":"Immunobiology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00716","article-title":"Gene-Dose Effect of MEFV Gain-of-Function Mutations Determines Ex Vivo Neutrophil Activation in Familial Mediterranean Fever","volume":"11","author":"Stoler","year":"2020","journal-title":"Front Immunol"},{"key":"B15","article-title":"Colchicine Modulates Expression of Pro-Inflammatory Genes in Neutrophils From Patients With Familial Mediterranean Fever and Healthy Subjects","volume":"27","author":"Manukyan","year":"2013","journal-title":"J Biol Regul Homeost Agents"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-013-2890-y","article-title":"Defect of Suppression of Inflammasome-Independent Interleukin-8 Secretion From SW982 Synovial Sarcoma Cells by Familial Mediterranean Fever-Derived Pyrin Mutations","volume":"41","author":"Sugiyama","year":"2014","journal-title":"Mol Biol Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02760","article-title":"Cellular Adaptation to Mechanical Stress: Role of Integrins, Rho, Cytoskeletal Tension and Mechanosensitive Ion Channels","volume":"119","author":"Matthews","year":"2006","journal-title":"J Cell Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00503.2005","article-title":"Cytoskeletal Remodeling and Cellular Activation During Deformation of Neutrophils Into Narrow Channels","author":"Yap","year":"1985","journal-title":"J Appl Physiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1602536","DOI":"10.1126\/sciadv.1602536","article-title":"Mechanical Deformation Induces Depolarization of Neutrophils","volume":"3","author":"Ekpenyong","year":"2017","journal-title":"Sci Adv"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780401023","article-title":"Criteria for the Diagnosis of Familial Mediterranean Fever","volume":"40","author":"Livneh","year":"1997","journal-title":"Arthritis Rheum"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.07.006","article-title":"Three Different Neutrophil Subsets Exhibited in Mice With Different Susceptibilities to Infection by Methicillin-Resistant Staphylococcus Aureus","volume":"21","author":"Tsuda","year":"2004","journal-title":"Immunity"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.151","article-title":"Homeostasis-Altering Molecular Processes as Mechanisms of Inflammasome Activation","volume":"17","author":"Liston","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01745","article-title":"The Pyrin Inflammasome in Health and Disease","volume":"10","author":"Schnappauf","year":"2019","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e61377","DOI":"10.1371\/journal.pone.0061377","article-title":"Human Neutrophil Cytoskeletal Dynamics and Contractility Actively Contribute to Trans-Endothelial Migration","volume":"8","author":"Stroka","year":"2013","journal-title":"PloS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12658","article-title":"Targeting Rho-GTPases in Immune Cell Migration and Inflammation","volume":"171","author":"Biro","year":"2014","journal-title":"Br J Pharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.067009","article-title":"Mechanical Signaling Through the Cytoskeleton Regulates Cell Proliferation by Coordinated Focal Adhesion and Rho Gtpase Signaling","volume":"124","author":"Provenzano","year":"2011","journal-title":"J Cell Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201746947","article-title":"Function and Mechanism of the Pyrin Inflammasome","volume":"48","author":"Heilig","year":"2018","journal-title":"Eur J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3RI0917-361R","article-title":"Neutrophil Heterogeneity: Bona Fide Subsets or Polarization States","volume":"103","author":"Deniset","year":"2018","journal-title":"J Leukoc Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.04.040","article-title":"Rhythmic Modulation of the Hematopoietic Niche Through Neutrophil Clearance","volume":"153","author":"Casanova-Acebes","year":"2013","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-05-718999","article-title":"Aged Neutrophils Contribute to the First Line of Defense in the Acute Inflammatory Response","volume":"128","author":"Uhl","year":"2016","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e12949","DOI":"10.1111\/eci.12949","article-title":"CXCR4, the Master Regulator of Neutrophil Trafficking in Homeostasis and Disease","volume":"48","author":"De Filippo","year":"2018","journal-title":"Eur J Clin Invest"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.03.005","article-title":"Aging: A Temporal Dimension for Neutrophils","volume":"37","author":"Adrover","year":"2016","journal-title":"Trends Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nature15367","article-title":"Neutrophil Ageing is Regulated by the Microbiome","volume":"525","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam9690","article-title":"Visualizing the Function and Fate of Neutrophils in Sterile Injury and Repair","volume":"358","author":"Wang","year":"2017","journal-title":"Science"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01958","article-title":"Expression, Role, and Regulation of Neutrophil Fc\u03b3 Receptors","volume":"10","author":"Wang","year":"2019","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/284759","article-title":"Rapid Decrease of CD16 (Fc\u03b3riii) Expression on Heat-Shocked Neutrophils and Their Recognition by Macrophages","volume":"2011","author":"Bzowska","year":"2011","journal-title":"J BioMed Biotechnol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq045","article-title":"Neutrophil Function in Inflammation and Inflammatory Diseases","volume":"49","author":"Wright","year":"2010","journal-title":"Rheumatol (Oxford)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3109\/14397595.2013.871108","article-title":"Neutrophil CD64 for Monitoring the Activity of Nontuberculous Mycobacteria Infection in Patients With Rheumatoid Arthritis","volume":"24","author":"Komiya","year":"2014","journal-title":"Mod Rheumatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.672728\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T05:54:54Z","timestamp":1621230894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.672728\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,17]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2021.672728"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.672728","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,17]]},"article-number":"672728"}}