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Mesenchymal stem cells enhance CCL8 expression by podocytes in lupus-prone MRL.Faslpr mice
Hyung Sook Kim1,2, Hong Kyung Lee1,3, Kihyeon Kim1
1College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 28160, Republic of Korea.
Abstract:
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.Faslpr 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.
Insights
Mesenchymal stem cells (MSCs) modulate nephritis by enhancing podocyte CCL8 production, which in turn boosts MSC immunosuppressive activity. This reveals a novel therapeutic pathway for lupus nephritis.
Area of Science:
- Immunology
- Nephrology
- Stem Cell Biology
Background:
- Systemic lupus erythematosus (SLE) frequently causes nephritis, characterized by immune and renal cell hyper-activation.
- Mesenchymal stem cells (MSCs) show therapeutic potential in nephritis by suppressing T and B cells, but their direct impact on renal cells remains unclear.
Purpose of the Study:
- To investigate the direct effects of MSCs on renal cells, focusing on chemokine expression in the context of lupus nephritis.
- To elucidate the mechanism by which MSCs influence chemokine production and its subsequent impact on MSC immunosuppressive function.
Main Methods:
- Analysis of chemokine expression (CCL2, CCL3, CCL4, CCL5, CCL8, CCL19, CXCL10) in kidneys of lupus-prone MRL.Faslpr mice at different ages.
- Assessment of MSCs' effect on chemokine expression in vivo and in vitro using renal cells (podocytes, tubular cells).
- Investigation of MSC-podocyte interaction using transwell assays and blocking antibodies (anti-VCAM-1).
- Evaluation of CCL8's role in modulating MSC immunosuppressive factor production (IL-10, IDO, TGF-β1, iNOS) and T cell IFN-γ inhibition.
Main Results:
- Chemokine expression, particularly CCL8, increased with age in lupus-prone mice kidneys.
- MSCs inhibited most chemokine increases but significantly upregulated CCL8 production by podocytes in a contact-dependent manner, mediated partly by VCAM-1.
- CCL8, in turn, enhanced MSCs' production of immunosuppressive factors and their ability to inhibit T cell activity.
Conclusions:
- MSCs promote CCL8 production in podocytes via cell-contact dependent mechanisms, a previously unrecognized interaction.
- Podocyte-derived CCL8 amplifies the immunosuppressive capacity of MSCs, suggesting a reciprocal regulatory loop.
- This study uncovers a novel therapeutic mechanism involving MSCs and podocyte-derived CCL8 in managing nephritis associated with SLE.
