Mesenchymal stem cells enhance CCL8 expression by podocytes in lupus-prone MRL.Fas lpr mice

• Published in: Scientific reports 2023-08, Vol.13 (1), p.13074
• Main Authors: Kim, Hyung Sook, Lee, Hong Kyung, Kim, Kihyeon, Ahn, Gi Beom, Kim, Min Sung, Lee, Tae Yong, Son, Dong Ju, Kim, Youngsoo, Hong, Jin Tae, Han, Sang-Bae
• Format: Article
• Language: English
• Subjects: Animals; Chemokines - metabolism; Lupus Erythematosus, Systemic; Lupus Nephritis; Mesenchymal Stem Cells; Mice; Mice, Inbred MRL lpr; Podocytes - metabolism
• ISSN: 2045-2322

Nephritis is common in systemic lupus erythematosus patients and is associated with hyper-activation of immune and renal cells. Although mesenchymal stem cells (MSCs) ameliorate nephritis by inhibiting T and B cells, whether MSCs directly affect renal cells is unclear. To address this issue, we examined the direct effect of MSCs on renal cells with a focus on chemokines. We found that expression of CCL2, CCL3, CCL4, CCL5, CCL8, CCL19, and CXCL10 increased 1.6-5.6-fold in the kidney of lupus-prone MRL.Fas mice with advancing age from 9 to 16 weeks. Although MSCs inhibited the increase in the expression of most chemokines by 52-95%, they further increased CCL8 expression by 290%. Using renal cells, we next investigated how MSCs enhanced CCL8 expression. CCL8 was expressed by podocytes, but not by tubular cells. MSCs enhanced CCL8 expression by podocytes in a contact-dependent manner, which was proved by transwell assay and blocking with anti-VCAM-1 antibody. Finally, we showed that CCL8 itself activated MSCs to produce more immunosuppressive factors (IL-10, IDO, TGF-β1, and iNOS) and to inhibit more strongly IFN-γ production by T cells. Taken together, our data demonstrate that MSCs activate podocytes to produce CCL8 in a contact-dependent manner and conversely, podocyte-derived CCL8 might potentiate immunosuppressive activity of MSCs in a paracrine fashion. Our study documents a previously unrecognized therapeutic mechanism of MSCs in nephritis.