- Conforti-Andreoni, C. et al. Uric acid-driven Th17 differentiation requires inflammasome-derived IL-1 and IL-18.Journal of Immunology 187, 5842–5850 (2011). | article
Wednesday, May 9, 2012
Singapore - Immunology: Guiding the immune response
Uric acid released from dying cells is a key driver of autoimmune diseases
When a cell dies, it secretes uric acid into its local environment to signal danger to the surrounding cells. Alessandra Mortellaro at the A*STAR Singapore Immunology Network and co-workers1 have discovered that uric acid interacts with other immune signals to drive the maturation of immune cells of a particular lineage that has been linked to autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
T helper 17 (Th17) cells are a subset of immune cells that secrete the proinflammatory cytokine interleukin-17 (IL-17). These cells fight foreign pathogens such as bacteria, but they also play a key role in driving many different autoimmune diseases. Determining the signaling molecules that drive Th17 maturation could lead to new therapeutic approaches for autoimmune diseases.
Previous studies have demonstrated the ability of uric acid to activate inflammation, but its role in the maturation of T cells has not been explored. When the researchers treated immature immune cells that they obtained from mouse lymph nodes with uric acid alone, the immune cells did not mature into the lineage of immune cells linked to autoimmune diseases. However, treatment with both uric acid and a second stimulus that drives the proinflammatory 'NF-κB' signaling pathway caused the immune cells to express Th17-related genes and secrete Th17-related cytokines, including IL-17.
Uric acid and the NF-κB signaling pathway have both been shown to induce the formation of an intracellular signaling complex called the inflammasome. Activation of the inflammasome leads to the secretion of the cytokines IL-1 and IL-18. Mortellaro and co-workers showed that uric acid and NF-κB-inducing stimuli were not able to induce Th17 maturation in mice lacking various components of the intracellular inflammasome complex. In addition, they found that IL-1 and IL-18 were required for Th17 maturation induced by uric acid and NF-κB signaling, as demonstrated by the fact that mice in which these two cytokines were absent produced less IL-17 than normal mice.
The findings suggest that tissue damage-induced release of uric acid, in combination with invasion of pathogens that activate NF-κB signaling, could lead to the skewing of immune responses along the Th17 lineage. This could then predispose individuals to autoimmune diseases. Because the inflammasome is responsible for the guidance of Th17 immune cell maturation by these stimuli, inhibiting the inflammasome could represent a strategy to block Th17 cell formation. “Our findings are important and might open up new therapeutic approaches to treat autoimmune disease,” explains Mortellaro.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network