Regulation of inflammation and fibrosis by macrophages in lymphedema.
Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b-diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4(+) cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4(+) cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function.
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Swapna
S
Ghanta
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Daniel A
DA
Cuzzone
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Jeremy S
JS
Torrisi
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Nicholas J
NJ
Albano
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Walter J
WJ
Joseph
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Ira L
IL
Savetsky
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Jason C
JC
Gardenier
The Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Chicago Medical Center, Chicago, Illinois.
David
D
Chang
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York;
Jamie C
JC
Zampell
The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; mehrarab@mskcc.org.
Babak J
BJ
Mehrara
D000818:Animals; D001706:Biopsy; D016026:Bone Marrow Transplantation; D016022:Case-Control Studies; D002454:Cell Differentiation; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D042601:Lymphatic Vessels / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008209:Lymphedema / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D014916:Whole-Body Irradiation
C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse
diphtheria toxin; fibrosis; inflammation; lymphatic function; lymphedema; macrophages