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Cited by 235Lymphatic System and DiseasesLymphatic Disorders and TreatmentsParasitic Diseases Research and Treatment

CD4+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis

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Zampell, Jamie C., Yan, Alan, Elhadad, Sonia, Avraham, Tomer, Weitman, Evan, Mehrara, Babak J.·2012·PLoS ONE
DOI 10.1371/journal.pone.0049940PMC PMC3502174
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Abstract

INTRODUCTION: Lymphedema is a chronic disorder that occurs commonly after lymph node removal for cancer treatment and is characterized by swelling, fibrosis, inflammation, and adipose deposition. Although previous histological studies have investigated inflammatory changes that occur in lymphedema, the precise cellular make up of the inflammatory infiltrate remains unknown. It is also unclear if this inflammatory response plays a causal role in the pathology of lymphedema. The purpose of this study was therefore to characterize the inflammatory response to lymphatic stasis and determine if these responses are necessary for the pathological changes that occur in lymphedema. METHODS: We used mouse-tail lymphedema and axillary lymph node dissection (ANLD) models in order to study tissue inflammatory changes. Single cell suspensions were created and analyzed using multi-color flow cytometry to identify individual cell types. We utilized antibody depletion techniques to analyze the causal role of CD4+, CD8+, and CD25+ cells in the regulation of inflammation, fibrosis, adipose deposition, and lymphangiogenesis. RESULTS: Lymphedema in the mouse-tail resulted in a mixed inflammatory cell response with significant increases in T-helper, T-regulatory, neutrophils, macrophages, and dendritic cell populations. Interestingly, we found that ALND resulted in significant increases in T-helper cells suggesting that these adaptive immune responses precede changes in macrophage and dendritic cell infiltration. In support of this we found that depletion of CD4+, but not CD8 or CD25+ cells, significantly decreased tail lymphedema, inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells significantly increased lymphangiogenesis both in our tail model and also in an inflammatory lymphangiogenesis model. CONCLUSIONS: Lymphedema and lymphatic stasis result in CD4+ cell inflammation and infiltration of mature T-helper cells. Loss of CD4+ but not CD8+ or CD25+ cell inflammation markedly decreases the pathological changes associated with lymphedema. In addition, CD4+ cells regulate lymphangiogenesis during wound repair and inflammatory lymphangiogenesis.

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  • CD4+ T cells and cytokine signaling are critical to the regulation of fibrosis and swelling in the mouse tail wound model of lymphedema.

    “CD4+ T cells and cytokine signaling are critical to the regulation of fibrosis and swelling in the mouse tail wound model of lymphedema (140, 141).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [140]

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Authors
Zampell, J. C., Yan, A., Elhadad, S., Avraham, T., Weitman, E., & Mehrara, B. J.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Mehrara, Babak J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-11-20
Volume
7
Issue
11
Pages
e49940
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0049940
PMC
PMC3502174
OpenAlex
W1967292619
Cited by
235
References
1
Citations by year
2026: 15 · 2025: 21 · 2024: 20 · 2023: 30 · 2022: 25 · 2021: 19 · 2020: 20 · 2019: 17 · 2018: 13 · 2017: 15 · 2016: 14 · 2015: 10 · 2014: 11 · 2013: 4
FWCI
3.96
Type
journal article
Language
en
Update notices
correction (2013-05-24)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Heart, Lung, and Blood Institute (R01HL111130)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
  • Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
Keywords
lymphedema, lymphatic stasis, CD4+ T cells, lymphangiogenesis, fibrosis, T helper cells, regulatory T cells, axillary lymph node dissection, inflammation, wound healing, lymph
MeSH terms
Animals, Fibrosis, Flow Cytometry, T-Lymphocytes, Helper-Inducer, Humans, Inflammation, Lymph Nodes, Lymphedema, Tail, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Lymphangiogenesis, Mice, Interleukin-2 Receptor alpha Subunit, Adaptive Immunity, Single-Cell Analysis

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