Increased Tim-3+ monocytes/macrophages are associated with disease severity in patients with IgA nephropathy

Abstract

T-cell immunoglobulin and mucin-domain-containing protein-3 (Tim-3) plays multiple important roles in immune response and participates in the pathogenesis of various inflammatory diseases by regulating macrophage polarization. However, its functions in the development of IgA nephropathy (IgAN) are still unclear. In this study, changes in the relative levels of Tim-3⁺ monocytes/macrophages in peripheral blood and renal tissue, and their clinical significance in patients with IgAN were investigated. The expression of CD68 and Tim-3 in macrophages from patients with IgAN was determined via immunohistochemistry and immunofluorescence staining assays. Peripheral blood of 48 patients with biopsy-proven IgAN and 18 healthy controls (HCs) was collected to determine the frequency of circulating CD14⁺Tim-3⁺ cells using flow cytometry, before and after 24 weeks of prednisolone treatment. Serum interleukin (IL)-10 and tumor necrosis factor α (TNF-α) levels were measured using enzyme-linked immunosorbent assays. The potential association between clinical signs and Tim-3⁺ monocytes/macrophages was analyzed. The percentages of circulating CD14⁺Tim-3⁺ monocytes were higher in samples from patients with IgAN than in those from HCs and were positively associated with the pathological features (segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis) of IgAN, according to the Oxford classification. Tissue staining assays revealed cells positive for both CD68 and Tim-3 in tubulointerstitial lesions of IgAN patients. In addition, elevated levels of serum IL-10 and TNF-α were detected in these patients in comparison to HCs. Furthermore, the frequency of circulating CD14⁺Tim-3⁺ monocytes had a positive correlation with levels of 24-h urinary protein and serum IL-10, and was negatively associated with renal function. After 24 weeks of treatment with prednisolone, the percentages of CD14⁺Tim-3⁺ cells were significantly reduced. In summary, our findings indicate that Tim-3⁺ monocytes/macrophages might be involved in the pathogenesisof IgAN and could be used as a potential indicator to evaluate disease severity.

Keywords: IgA nephropathy; Monocyte/macrophages; Tim-3.