Beyond DNA repair, the immunological role of PARP ‐1 and its siblings

Summary ADP ‐ribosylation is the addition of one or more (up to some hundreds) ADP ‐ribose moieties to acceptor proteins. There are two major families of enzymes that catalyse this reaction: extracellular ADP ‐ribosyl‐transferases ( ART s), which are bound to the cell membrane by a glycosylphosphatidylinositol anchor or are secreted, and poly( ADP ‐ribose)‐polymerases ( PARP s), which are present in the cell nucleus and/or cytoplasm. Recent findings revealed a wide immunological role for ADP ‐ribosylating enzymes. ART s, by sensing extracellular NAD concentration, can act as danger detectors. PARP ‐1, the prototypical representative of the PARP family, known to protect cells from genomic instability, is involved in the development of inflammatory responses and several forms of cell death. PARP ‐1 also plays a role in adaptive immunity by modulating the ability of dendritic cells to stimulate T cells or by directly affecting the differentiation and functions of T and B cells. Both PARP ‐1 and PARP ‐14 (CoaSt6) knockout mice were described to display reduced T helper type 2 cell differentiation and allergic responses. Our recent findings showed that PARP ‐1 is involved in the differentiation of Foxp3 + regulatory T (Treg) cells, suggesting a role for PARP ‐1 in tolerance induction. Also ART s regulate Treg cell homeostasis by promoting Treg cell apoptosis during inflammatory responses. PARP inhibitors ameliorate immune‐mediated diseases in several experimental models, including rheumatoid arthritis, colitis, experimental autoimmune encephalomyelitis and allergy. Together these findings show that ADP ‐ribosylating enzymes, in particular PARP ‐1, play a pivotal role in the regulation of immune responses and may represent a good target for new therapeutic approaches in immune‐mediated diseases.