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The adaptive immune system contributes to renal inflammation and diseases of both native and transplanted kidneys. Understanding the precise mechanisms of immune regulation in the kidney will lead to improved therapies for renal auto and alloimmune diseases. The kidney is an organ that specializes in molecular transport and contains a network of renal mononuclear phagocytes (rMPCs) that patrol the bloodstream for pathogens and other molecules. We hypothesized that the proximal tubule's transport function contributes to renal immune surveillance by reabsorbing and enhancing uptake of filtered antigens by major histocompatibility complex (MHCII)-expressing rMPCs. The cross-section between renal tubular transport and rMPC may be an important mechanism that, in the right circumstance, promotes antigen-specific immunity and inflammation in the kidney.
We used Cx3cr1GFP/+, Dpep1-/-, and wild-type C57BL6 mice loaded with fluorescent-conjugated ovalbumin (OVA) to explore antigen trafficking in the kidney. We utilized OTII T-cell receptor transgenic mice recognizing ovalbumin residues 323 to 339 to investigate CD4+ immune responses. Tubular reabsorption via dipeptidase-1 (DPEP1) and LRP2 was inhibited using cilastatin (cila,50 mg/kg). Acute kidney injury was induced by ischemia-reperfusion or IRI (30 minutes at 37°C). Cellular behavior was analyzed using fluorescent antibodies, intravital microscopy (IVM), and flow cytometry (FC). Statistical analyses included T-tests, ANOVA, and Bonferroni’s post-test.
IVM and FC analyses in C57BL6 mice confirmed the presence of a network of stellate cells or rMPCs (CD45+, CX3CR1high, CD11b+, F4/80high, CD11c+, and MHCIIhigh) closely interacting with renal vasculature and tubules. Significant OVA uptake by rMPC was observed within minutes of systemic administration. In vivo, OVA uptake by dendritic cells (DCs, CD45+CD11c+MHCII+) in the kidney was higher compared to liver and spleen DCs. However, at equivalent OVA concentrations in vitro, kidney, liver, and spleen DCs efficiently absorbed OVA confirming that the kidney possessed a unique ability to enhance DC antigen uptake. Blocking tubular reabsorption with cila reduced OVA uptake in renal tubules and DCs. No significant changes were observed when studying OVA trafficking in Dpep1-/- mice, suggesting that LRP2, but not DPEP1 might have contributed to tubular antigen transport. We further explored DC behavior during tubular cell death induced by ischemia/reperfusion, finding elevated CD86 expression in DCs after 24 hours of reperfusion. Finally, we investigated the implications of renal luminal antigen surveillance in OTII mice. The presence of both antigen and DC activation by IRI resulted in tubulointerstitial inflammation consisting of Th1 and Th17 CD4+ T cells. Inhibiting tubular transport with cila reduced CD4+ T cell activation and infiltration in the kidney.
In summary, our findings highlight the vital role of tubular transport in efficiently reabsorbing and monitoring filtered antigens within the kidney. This immune surveillance likely fosters peripheral tolerance under normal conditions but it may stimulate adaptive T cell responses and renal inflammation in proinflammatory scenarios. A deeper understanding of these mechanisms holds promise for innovative therapies targeting autoimmune and alloimmune kidney diseases.