Purinergic signalling in inflammation of the central nervous system Francesco Di Virgilio 1 , Stefania Ceruti 2 , Placido Bramanti 3 and Maria P. Abbracchio 2 1 Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, 44100 Ferrara, Italy 2 Department of Pharmacological Sciences, Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, University of Milan, 20133 Milan, Italy 3 IRCCS Centro Neurolesi ‘Bonino-Pulejo’, 98124 Messina, Italy Inflammation is the most fundamental body reaction to noxious stimuli. No vascularized tissue, organ or appar- atus is free from this response. Several mediators of inflammation, originating from outside (exogenous) or inside (endogenous) the body, are known. Among the endogenous factors, extracellular nucleotides and nucleosides are attracting interest for their ubiquity and striking ability to modulate diverse immune responses. Until recently, it was doubted that the central nervous system (CNS), reportedly an ‘immunoprivileged organ’, could be the site of immune reactions. Nowa- days, it is acknowledged that inflammation and immu- nity have a key role in a vast range of CNS diseases. Likewise, it is clear that purinergic signalling profoundly affects neuroinflammation. Here, we provide a brief update of the state of the art in this expanding field. Introduction Inflammation is a complex homeostatic mechanism devised to protect the integrity of the organism against endogenous or exogenous noxious agents. It is usually considered an aspect of innate immunity or, according to some, innate immunity tout court [1,2]. Inflammation has been known to physicians for over two thousand years and its basic manifestations (cardinal signs) calor (warmth), dolor (pain), tumor (swelling) and rubor (redness) were clearly identified by Aulus Cornelius Celsus in the early years of the Christian age. Calor, dolor, tumor and rubor describe and summarize all the crucial events occurring in a tissue during the inflammatory response. Players of inflammation are cells and soluble factors. The family of inflammatory cells has now grown to include cell types as different as fibroblasts, endothelial cells and adipocytes besides the typical circulating and resident leukocytes and tissue mast cell [2]. However, their increase in number is negligible if compared to the exponential growth of novel soluble inflammatory mediators, now num- bering in hundreds. Among these, extracellular adenine and uracil nucleotides (e.g. ATP and UTP) and nucleosides (e.g. adenosine) acting at P2 or P1 purinergic receptors are relative new-comers in the field [3,4]. In addition, enzymes that degrade extracellular nucleotides, such as ectoATP/ ADPases (CD39) and ectoAMPase (CD73), also have a profound immunomodulatory activity [5]. Here, as a follow up to the first [6] of a series of articles dealing with purinergic signalling in the central nervous system (CNS), we summarize data highlighting a pivotal role for this system in alerting and tuning immune and inflam- matory reactions to aversive influences in the CNS. We also highlight recent developments that implicate puriner- gic signalling in acute and chronic neurodegenerative dis- eases, hoping that a better understanding of the role of extracellular purines and pyrimidines in neuroinflamma- tion will lead to the development of novel therapies. A brief history of purinergic signalling in inflammation Many metabolites and the enzymes responsible for their generation (e.g. nitric oxide and the inducible nitric oxide synthase, arginine and arginase, tryptophan metabolites and indoleamine deoxygenase, lipoxins and lipoxigenase and, more recently, nucleotides, adenosine and their meta- bolizing enzymes, i.e. CD39 and CD73) are now regarded as true inflammatory mediators. Players in purinergic signalling are extracellular nucleotides, adenosine, CD39 and CD73. Here, we only focus on the role of nucleotides in inflammation; for adenosine, CD39 and CD73 the reader is referred to recent exhaustive reviews [7–10]. Indications of an involvement of extracellular ATP in systemic inflammation date back to the 1970 s when Dahl- quist and Diamant [11] reported its strong histamine- releasing action from rat mast cells. Cockcroft and Gomperts [12] later postulated expression by mast cells of a specific ATP receptor, which was later identified as the P2X 7 re- ceptor. These early observations were followed by scattered reports of the ability of this nucleotide to produce responses in lymphocytes, monocytes and polymorphonuclear gra- nulocytes (for review, see Ref. [13]). However, the notion that extracellular ATP might participate in inflammation gained acceptance very slowly, at least until P2 receptors were cloned and their expression by inflammatory cells was fully characterized. The turning point was the discovery of the strong linkage of one of the P2 receptors (the ATP-gated P2X 7 receptor channel) to maturation and secretion of the key cytokine interleukin (IL)-1b [14–16] and the in vivo demonstration that ATP is present in high levels in the extracellular space during inflammation [17,18]. To date, a thorough characterization has been made of P2 receptor expression, not only of the seven subtypes of ligand-gated P2X 1 –P2X 7 receptor but also of the P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 G-protein-coupled Review Corresponding author: Di Virgilio, F. (fdv@unife.it) 0166-2236/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2008.11.003 Available online 8 January 2009 79