Dynamics of Immune Cell Infiltration and Fibroblast-Derived IL-33/ST2 Axis Induction in a Mouse Model of Post-Surgical Lymphedema

Lymphedema is an intractable disease most commonly associated with lymph node dissection for cancer treatment and can lead to a decreased quality of life. Type 2 T helper (Th2) lymphocytes have been shown to be important in the progression of lymphedema. The activation of IL-33 and its receptor, the suppression of tumorigenicity 2 (ST2) signaling pathway, induces the differentiation of Th2 cells, but its involvement in lymphedema remains unclear. In the present study, we analyzed the dynamics of immune cell infiltration, including the IL-33/ST2 axis, in a mouse tail lymphedema model. Neutrophil infiltration was first detected in the lymphedema tissue on postoperative day (POD) 2. Macrophage infiltration increased from POD 2 to 5. The number of CD4⁺ T cells, including 50% Tregs, gradually increased from POD 14. The mRNA expression of <i>ll13</i> and <i>Ifng</i> increased on POD 21. The expression of IL-33 was induced in fibroblast nuclei within dermal and subcutaneous tissues from POD 2, and the expression of the <i>Il1rl1</i> gene encoding ST2 increased from POD 7. We demonstrated the infiltration process from innate to acquired immune cells through the development of a mouse tail lymphedema. The IL-33/ST2 axis was found to be induced during the transition from innate to acquired immunity.