Dimitrios Balomenos
National Center for Biotechnology/CSIC, Madrid, Spain.
Title: P21 is a master regulator of nf-kb-dependent inflammation in immune disease and allergic asthma
Biography
Biography: Dimitrios Balomenos
Abstract
Decontrolled inflammatory responses induce live-threatening disease or aggravate autoimmunity or allergy. p21 was first identified as an inhibitor of and cyclin-dependent kinase 2 inhibitor (CDK2). However, other functions are now attributed to p21, as it orchestrates unique anti-inflammatory functions.
p21 controls NF-κB activation, macrophage activation and LPS-induced septic shock. In the absence of p21, LPS treatment leads to increased NF-κB activation, macrophage overstimulation and excessive inflammatory production. Upon extreme TLR4 activation, macrophage hyperactivation is also controlled by reprograming of hyperinflammatory microphages (M1) to a hyporesponsive status (M2-like) after a secondary LPS challenge, which is known as endotoxin tolerance. We recently reported that p21 promotes M1-to-M2 polarization, as p21-/- macrophages showed impaired ability to reprogram. p21 shifts the balance between active p65/p50 and inhibitory p50/p50 NF‑ï«B and promotes macrophage reprogramming by favoring DNA-binding affinity of p50/p50 homodimers, which limit IFN-ï¢ production. The first association of p21 with the immune response was its identification as an autoimmunity suppressor, and it was assumed to control T cell proliferation. However, our latest findings show that lack of p21 drives lupus-like disease by augmenting the activation status of T cells The major characteristic of this hype activation is the elevated production of IFN-gamma by T cells, a major inducer of lupus autoimmunity. Our findings point to p21 as an early regulator of T cell activation that controls mitochondrial ROS production. Finally, in agreement with effect of p21 on the excessive immune responses, p21-deficient mice developed extreme allergic asthma when subjected to the allergy-inducing OVA model, exhibiting severe pneumonitis and striking perivascular and interstitial inflammation compare to controls. Overall p21 emerges as a global guardian of hyperresponsivess in inflammatory, autoimmune and allergic pathologies at both the macrophage and T cell levels.