PDGFRα promotes organ resistance to immune-mediated damage

Abstract

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that exhibits great clinical heterogeneity. Development and clinical expression of autoimmune diseases is strongly influenced by genetic variants. The single nucleotide polymorphism (SNP) rs1364989, located close to PDGFRA, has been associated with the development of lupus nephritis through an unknown mechanism. Because PDGF, through its α and β receptors, regulates tissue response to inflammation, we hypothesized that rs1364989 could modulate the behavior of renal cells in the context of immune-mediated glomerulonephritis. To determine whether rs1364989 affects the expression of PDGFRα, we analyzed umbilical cord mesenchymal cells from carriers of risk and protective alleles. We observed that the presence of the risk allele was associated with reduced PDGFRα expression. Next, we analyzed whether inflammatory mediators could modulate PDGFRα expression in in vitro and in vivo settings. We documented that its levels increase during acute inflammation in a murine model of glomerulonephritis. In vitro, this effect could be reproduced by IL-17. Absence of PDGFRα increased kidney damage during immune complex-induced glomerulonephritis. An analogous effect was observed in joints of mice with collagen-induced arthritis. Our results demonstrate that the SLE-associated allele of rs1364989 reduces the expression of PDGFRα and that this receptor may activate a pathway that protects tissues in response to local inflammation. These findings highlight the importance of tissue resilience as a factor that can protect an organ from inflammatory damage in the setting of autoimmunity. This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico