CoChat
Sign Up
Cited by 0

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

RAC2 orchestrates immune cell actin remodeling and migration

Berthiaume Fox, Kayleigh A., Galvin, Emily R., Gurtner, Geoffrey C., Chen, Kellen·2026·Frontiers in Immunology
DOI 10.3389/fimmu.2026.1917716
Open this paper in CoChat — free account

Abstract

In this review, we comprehensively summarize how RAC2+ innate immune cells contribute to a spectrum of immune dysregulation and disease states across multiple organ systems in humans. Our lab has recently identified RAC2’s critical role in immune cell biology in the context of human and murine wound healing and fibrosis, induced by aberrant mechanical signaling. Thus, we sought to investigate the role of RAC2 in human immune cells. Here, we summarize the effects of gain-of-function (GOF), loss-of-function (LOF), and null RAC2 mutations on neutrophil phenotypes. As such, we propose a novel mechanism for RAC2-dependent biphasic neutrophil migration, critical for these cells in migrating to sites of injury across many disease states, including wound healing and fibrosis. Innate immune cells circulate and home to injury sites during the initial healing phases in all organs, therefore, understanding RAC2 regulation of neutrophil functions may reveal new avenues for systemic immunomodulatory therapies to treat immune dysregulation, and to better characterize mechanisms of wound healing and fibrosis.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fimmu.2026.1917716

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 76

  1. Duscher, 2014, Mechanotransduction and fibrosis, J Biomech, 47, 1997, 10.1016/j.jbiomech.2014.03.031 · DOI
  2. Wong, 2011, Pushing back: wound mechanotransduction in repair and regeneration, J Invest Dermatol, 131, 10.1038/jid.2011.212 · DOI
  3. Wong, 2011, Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling, Nat Med, 18, 10.1038/nm.2574 · DOI · Paper page
  4. Rustad, 2013, The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation, Differentiation, 86, 87, 10.1016/j.diff.2013.02.003 · DOI
  5. Wong, 2014, Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing, Ann Surg, 260, 10.1097/SLA.0000000000000219 · DOI
  6. Gurtner, 2011, Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies, Ann Surg, 254, 10.1097/SLA.0b013e318220b159 · DOI
  7. Januszyk, 2014, Mechanical offloading of incisional wounds is associated with transcriptional downregulation of inflammatory pathways in a large animal model, Organogenesis, 10, 10.4161/org.28818 · DOI · Paper page
  8. Lim, 2014, The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial, Plast Reconstr Surg, 133, 398, 10.1097/01.prs.0000436526.64046.d0 · DOI
  9. Longaker, 2014, A randomized controlled trial of the embrace advanced scar therapy device to reduce incisional scar formation, Plast Reconstr Surg, 134, 10.1097/PRS.0000000000000417 · DOI
  10. Chen, 2021, Disrupting biological sensors of force promotes tissue regeneration in large organisms, Nat Commun, 12, 5256, 10.1038/s41467-021-25410-z · DOI
  11. Chen, 2022, Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting, Sci Transl Med, 14, 10.1126/scitranslmed.abj9152 · DOI
  12. Chen, 2022, Mechanical strain drives myeloid cell differentiation toward proinflammatory subpopulations, Adv Wound Care (New Rochelle), 11, 10.1089/wound.2021.0036 · DOI
  13. Padmanabhan, 2023, Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells, Nat BioMed Eng, 7, 10.1038/s41551-023-01091-5 · DOI
  14. Chen, 2025, Targeting circulating mechanoresponsive monocytes and macrophages to reduce fibrosis, Nat BioMed Eng, 10, 10.1038/s41551-025-01479-5 · DOI
  15. Etienne-Manneville, 2002, Rho GTPases in cell biology, Nature, 420, 10.1038/nature01148 · DOI · Paper page
  16. Dufies, 2021, RhoGTPases and inflammasomes: Guardians of effector-triggered immunity, PloS Pathog, 17, 10.1371/journal.ppat.1009504 · DOI
  17. Zhang, 2022, Combined immunodeficiency caused by a novel de novo gain-of-function RAC2 mutation, J ClinImmunol, 42, 10.1007/s10875-022-01288-4 · DOI
  18. Smits, 2020, A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease, Clin Immunol, 212, 10.1016/j.clim.2019.108248 · DOI
  19. Hanson, 2026, Rac2 hyperactivity drives neutrophil degranulation, myeloperoxidase deficiency, and lymphopenia, openRxiv, 10.64898/2026.05.12.723629 · DOI
  20. Sharapova, 2019, Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections, Clin Immunol, 205, 1, 10.1016/j.clim.2019.05.003 · DOI
  21. Lougaris, 2019, A monoallelic activating mutation in RAC2 resulting in a combined immunodeficiency, J Allergy Clin Immunol, 143, 10.1016/j.jaci.2019.01.001 · DOI
  22. Williams, 2000, Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency, Blood, 96, 10.1182/blood.V96.5.1646 · DOI
  23. Ambruso, 2000, Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation, Proc Natl Acad Sci, 97, 10.1073/pnas.080074897 · DOI · Paper page
  24. Accetta, 2011, Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia, J Allergy Clin Immunol, 127, 10.1016/j.jaci.2010.10.013 · DOI · Paper page
  25. Roberts, 1999, Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense, Immunity, 10, 10.1016/s1074-7613(00)80019-9 · DOI · Paper page
  26. Li, 2002, Chemoattractant-stimulated Rac activation in wild-type and Rac2-deficient murine neutrophils: preferential activation of Rac2 and Rac2 gene dosage effect on neutrophil functions, J Immunol, 169, 10.4049/jimmunol.169.9.5043 · DOI · Paper page
  27. Alkhairy, 2015, RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency, J Allergy Clin Immunol, 135, 10.1016/j.jaci.2014.10.039 · DOI · Paper page
  28. Bahrami, 2022, Progressive multifocal leukoencephalopathy in a patient with novel mutation in the RAC2 gene: a case report, J Med Case Rep, 16, 235, 10.1186/s13256-022-03333-7 · DOI
  29. Forehand, 1991, Mechanisms of lipopolysaccharide priming for enhanced respiratory burst activity in human neutrophils, Adv Exp Med Biol, 297, 65, 10.1007/978-1-4899-3629-5_6 · DOI
  30. Belambri, 2018, NADPH oxidase activation in neutrophils: Role of the phosphorylation of its subunits, Eur J Clin Invest, 48, 10.1111/eci.12951 · DOI
  31. Heyworth, 1993, Regulation of NADPH oxidase activity by RAC GTPase-activating protein(s), Mol Biol Cell, 4, 10.1091/mbc.4.11.1217 · DOI
  32. Donkó, 2024, Clinical and functional spectrum of RAC2-related immunodeficiency, Blood, 114, 10.1182/blood.2023022098 · DOI · Paper page
  33. Kurkchubasche, 2001, Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease, J Pediatr, 139, 10.1067/mpd.2001.114718 · DOI · Paper page
  34. Heyworth, 1993, Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558, J Biol Chem, 269, 10.1016/S0021-9258(18)47341-3 · DOI
  35. Fattouh, 2013, Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection, PloS One, 8, 10.1371/journal.pone.0061629 · DOI
  36. Faroudi, 2010, Critical roles for Rac GTPases in T-cell migration to and within lymph nodes, Blood, 116, 10.1182/blood-2010-08-299438 · DOI
  37. Croker, 2002, The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes, J Immunol, 168, 10.4049/jimmunol.168.7.3376 · DOI
  38. Ojha, 2008, Assessment of wound-site redox environment and the significance of Rac2 in cutaneous healing, Free Radical Biol Med, 44, 10.1016/j.freeradbiomed.2007.10.056 · DOI
  39. Lorès, 1997, Enhanced apoptosis in the thymus of transgenic mice expressing constitutively activated forms of human Rac2GTPase, Oncogene, 15, 10.1038/sj.onc.1201378 · DOI · Paper page
  40. Sato, 2013, Molecular mechanisms of N-formyl-methionyl-leucyl-phenylalanine-induced superoxide generation and degranulation in mouse neutrophils: phospholipase D is dispensable, Mol Cell Biol, 33, 10.1128/mcb.00869-12 · DOI
  41. Korchak, 2007, Selective roles for alpha-PKC in positive signaling for O-(2) generation and calcium mobilization but not elastase release in differentiated HL60 cells, BBA- Mol Cell Res, 1773, 10.1016/j.bbamcr.2006.10.007 · DOI
  42. Thompson, 1993, The chemotactic factor N-formylmethionyl-leucyl-phenylalanine activates microtubule-associated protein 2 (MAP) kinase and a MAP kinase kinase in polymorphonuclear leucocytes, Biochem J, 290, 10.1042/bj2900483 · DOI
  43. Damascena, 2022, Neutrophil activated by the famous and potent PMA (phorbol myristate acetate), Cells, 11, 10.3390/cells11182889 · DOI
  44. Kim, 2001, Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways, J Immunol, 166, 10.4049/jimmunol.166.2.1223 · DOI · Paper page
  45. Granfeldt, 2002, Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane- and granule-localized NADPH-oxidase, J Leukocyte Biol, 71, 10.1189/jlb.71.4.611 · DOI
  46. Seguchi, 2002, Study of NADPH oxidase-activated sites in human neutrophils, J Electron Microsc, 51, 87, 10.1093/jmicro/51.2.87 · DOI
  47. Bréchard, 2008, Regulation of superoxide production in neutrophils: role of calcium influx, J Leukocyte Biol, 84, 10.1189/jlb.0807553 · DOI
  48. Dorseuil, 1992, Inhibition of superoxide production in B lymphocytes by rac antisense oligonucleotides, J Biol Chem, 267, 10.1016/S0021-9258(19)36716-X · DOI
  49. Hamilton, 2021, Therapeutic assessment of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in reducing periprosthetic joint infection, Eur Cells Mater, 42, 10.22203/ecm.v042a09 · DOI
  50. Lee, 2023, Formyl peptide receptor 2 is an emerging modulator of inflammation in the liver, Exp Mol Med, 55, 10.1038/s12276-023-00941-1 · DOI
  51. Liu, 2012, Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes, Sci Rep, 2, 10.1038/srep00786 · DOI
  52. Ray, 2006, Uteroglobin suppresses allergen-induced TH2 differentiation by down-regulating the expression of serum amyloid A and SOCS-3 genes, FEBS Lett, 580, 10.1016/j.febslet.2006.09.059 · DOI
  53. Berthiaume Fox, 2026, From respiratory infections to environmental exposures: CC16 is a key modulator of airway homeostasis, Front Med, 13, 10.3389/fmed.2026.1869095 · DOI
  54. Cano, 1991, Kinetic analysis of F-actin depolymerization in polymorphonuclear leukocyte lysates indicates that chemoattractant stimulation increases actin filament number without altering the filament length distribution, J Cell Biol, 115, 10.1083/jcb.115.3.677 · DOI
  55. Zigmond, 1974, Mechanisms of sensing chemical gradients by polymorphonuclear leukocytes, Nature, 249, 10.1038/249450a0 · DOI
  56. Lacy, 2011, Agonist activation of F-actin-mediated eosinophil shape change and mediator release is dependent on Rac2, Int Arch Allergy Immunol, 156, 10.1159/000322597 · DOI
  57. Sun, 2007, Rac1 and Rac2 differentially regulate actin free barbed end formation downstream of the fMLP receptor, J Cell Biol, 179, 10.1083/jcb.200705122 · DOI
  58. Zhang, 2009, Human neutrophils coordinate chemotaxis by differential activation of Rac1 and Rac2, J Immunol, 183, 10.4049/jimmunol.0900849 · DOI · Paper page
  59. Evangelista, 1996, Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: Evidence of adhesion cascade and cross talk between P-selectin and the B2 integrin CD11b/CD18, Blood, 88, 10.1182/blood.V88.11.4183.4183 · DOI
  60. Wang, 2019, Actomyosin contractility-dependent matrix stretch and recoil induces rapid cell migration, Nat Commun, 10, 10.1038/s41467-019-09121-0 · DOI
  61. Klank, 2017, Biphasic dependence of glioma survival and cell migration on CD44 expression level, Cell Rep, 18, 23, 10.1016/j.celrep.2016.12.024 · DOI
  62. DiMilla, 1991, Mathematical model for the effects of adhesion and mechanics on cell migration speed, Biophys J, 60, 15, 10.1016/s0006-3495(91)82027-6 · DOI
  63. Zaman, 2006, Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis, Proc Natl Acad Sci, 103, 10.1073/pnas.0604460103 · DOI
  64. Courjal, 1997, Structure and chromosomal assignment to 22q12 and 17qter of the ras-related Rac2 and Rac3 human genes, Genomics, 44, 10.1006/geno.1997.4871 · DOI
  65. Poli, 2025, Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee, J Hum Immun, 1, 10.70962/jhi.20250003 · DOI
  66. McCabe, 2002, Newborn screening: rationale for a comprehensive, fully integrated public health system, Mol Genet Metab, 77, 10.1016/s1096-7192(02)00196-8 · DOI
  67. 2020, MIM number: {602049}
  68. Doye, 2024, RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation, J Exp Med, 221, 10.1084/jem.20231562 · DOI · Paper page
  69. Sanger, 1977, Nucleotide sequence of bacteriophage ϕX174 DNA, Nature, 265, 10.1038/265687a0 · DOI
  70. Goh, 2012, Application of whole exome sequencing to identify disease-causing variants in inherited human diseases, Genomics Inf, 10, 10.5808/gi.2012.10.4.214 · DOI
  71. Stark, 2016, A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders, Genet Med, 18, 10.1038/gim.2016.1 · DOI
  72. Juarez, 2025, A machine learning decision support tool optimizes WGS utilization in a neonatal intensive care unit, NPJ Digital Med, 8, 10.1038/s41746-025-01458-9 · DOI
  73. Roos, 2010, Hematologically important mutations: X-linked chronic granulomatous disease (third update), Blood Cells Mol Dis, 45, 10.1016/j.bcmd.2010.07.012 · DOI
  74. Hanna, 2012, Leukocyte adhesion deficiencies, Ann N Y Acad Sci, 1250, 10.1111/j.1749-6632.2011.06389.x · DOI
  75. Jinek, 2018, A programmable dual RNA-guided DNA endonuclease in adaptive bacterial immunity, Science, 337, 10.1126/science.1225829 · DOI · Paper page
  76. Zhang, 2024, Base editors-mediated gene therapy in hematopoietic stem cells for hematologic diseases, Stem Cell Rev Rep, 20, 10.1007/s12015-024-10715-5 · DOI

Metadata

Authors
Berthiaume Fox, K. A., Galvin, E. R., Gurtner, G. C., & Chen, K.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2026-08-20
Volume
17
ISSN
1664-3224
DOI
10.3389/fimmu.2026.1917716
Cited by
0
References
4
Licence
creativecommons.org/licenses/by/4.0/ (vor)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review