P21 regulates common activation pathways in macrophages and t cells and acts as a suppressor of inflammatory and autoimmune syndromes

Resumen

Proinflammatory and anti-inflammatory immune reactions must be regulated precisely to maintain balance in the immune system. Excessive activation can result in hypersensitivity diseases such as autoimmunity or septic shock, leading to multiple organ dysfunction syndrome and death. Excessive anti-inflammatory activity is also harmful, as it can lock monocytes and macrophages into an unresponsive state. Here we identify a role for p21 as a negative regulator of activated T cells and macrophages, which is independent of the previously known p21 function as a cell cycle inhibitor. Our data show that p21 controls T cell activation and IFN-¿ production through negative regulation of mitochondrial reactive oxygen species (mROS) production. When we overexpressed p21 in T cells of lpr mice, we were able to reduce T cell production of IFN-¿, which led to amelioration of lupus-like disease in these mice. Further, we show that p21 negatively regulates LPS (lipopolysaccharide)-induced mROS production in macrophages. In the absence of p21, LPS-activated macrophages showed strong NF ¿B activation and increased IFN-ß secretion. As a consequence, p21-deficient macrophages showed impaired ability to reprogram their proinflammatory status to immunosuppression, known as LPS tolerance. Our findings point to a role for p21 in regulating the balance between active p65/p50 and inhibitory p50/p50 NF-¿B complexes during LPS tolerance in macrophages. Finally, we show that p21 is an important component of macrophage reprogramming in human monocytes, with implications in sepsis, and thus demonstrate the biological significance of our data.