ReviewPurinergic signaling in the immune system
Introduction
A main feature of a homeostatic system is the ability to rapidly sense any signs of distress that might signal the presence of a threat of exogenous or endogenous origin. This is even more important in the case of complex and integrated systems such as living organisms that are characterized by a continuous exchange of information with the external world and at the same time undergo a continuous process of internal self renewal, with the associated generation of new cells as well as elimination of the old ones. Such a homeostatic system must be equipped with a fine network of sensors that constantly monitor the internal environment to detect even the most subtle signs of injury or distress. Accordingly, a homeostatic system should be able to release an array of intracellular messengers capable of signaling cell and tissue damage. In a complex and integrated organism such a signaling network becomes more and more important, thus evolution has selected the easiest and at the same time most efficient signaling devices. The simplest way to signal cell distress is to develop a receptor system that senses in the extracellular space the presence of molecules that are normally sequestered intracellularly. Therefore, it is not a surprise that the most powerful and ubiquitous signal of distress or damage (otherwise known as DAMP, damage-associated molecular pattern) is ATP. Of course, ATP is by no means the only DAMP used by multicellular organisms to signal danger, but it is likely to be the most ancient.
In the healthy organism, ATP is almost exclusively present inside the cells, where it reaches a several millimolar concentration. In the extracellular environment the ATP concentration is negligible, i.e. in the low nanomolar range (Burnstock, 2007). The huge intra/extracellular concentration gradient on the one hand accelerates enormously the speed of release of ATP in response to the opening of plasma membrane ATP-conducing pathways, and on the other increases the signal-to-noise ratio, the background noise being almost nil. Furthermore, ATP is highly water soluble, and thus easily diffusible in the aqueous extracellular environment, and quickly degraded by a battery of powerful nucleotidases (Yegutkin, 2014). Last, but not the least, virtually all eukariotic cells are equipped with specific receptors for extracellular ATP, the P2 receptors (Burnstock, 2007). Thus, ATP is an ideal extracellular messenger of cellular distress and P2 receptors ideal sensors of danger. It has been proposed that adenosine, the most important ATP degradation product, might also be an important danger signal (Fredholm, 2007, Sitkovsky and Ohta, 2005), but given its mainly immunosuppressive activity, this nucleoside is more likely to intervene at later stages as an immunoregulatory feed-back mediator.
Section snippets
Purinergic receptors expressed by immune cells
Four P1 receptor (P1R) subtypes (A1, A2A, A2B and A3), eight P2Y (P2Y1, 2, 4, 6, 11, 12, 13, 14) and seven P2X (P2X1-7) subtypes are known (Burnstock, 2014, Chen et al., 2013, Khakh and North, 2006, North and Surprenant, 2000). Basically all P1 and P2 receptor subtypes are expressed by immune cells, in a cell type- and differentiation-dependent fashion. Adenosine P1 receptors are widely expressed by immune cells of the myeloid and lymphoid lineage. The role of A1 and A3 receptors is not well
Purinergic receptors play a crucial role as stimuli for chemotaxis of inflammatory cells
At the inception of inflammation DAMP signaling is essential to recruit inflammatory cells at the site of tissue damage or pathogen entry. Thus, nucleotides as the primordial DAMPs are anticipated to have chemotactic activity. There is formal proof that ATP is released to micromolar amounts at sites of inflammation or injury (Pellegatti et al., 2008, Weber et al., 2010). Similar demonstration for other nucleotides is lacking, but it is reasonable to believe that their release parallels that of
Extracellular purines and Ag recognition and destruction
As expected from a bona fide DAMP, ATP modulates DC functions in multiple fashions. DCs are known to skew CD4+ T lymphocyte differentiation towards a Th1, Th2, Th17 or Treg phenotype (Walsh and Mills, 2013). Several factors are understood to affect this process, among which adenosine and extracellular ATP seem to play an important role (la Sala et al., 2001, Panther et al., 2003). The inflammatory microenvironment is rich in extracellular ATP that, in conjunction with other pro-inflammatory
Conclusion
Although purinergic signaling was initially thought to be an essential and physiologically relevant signaling pathway exclusively in the nervous system, it is increasingly evident that it also plays an essential, possibly even more important, role in the immune and inflammatory systems. A literature (December 2014) search linking “purinergic receptors” to inflammation or immunity yielded over 1650 hits, while a similar search linking “purinergic receptors” to central or peripheral nervous
Acknowledgments
FDV is supported by grants from the Italian Association for Cancer Research (n. IG 5354), Telethon of Italy (n. GGP06070), ERA-NET Neuron Joint Transnational Project “Nanostroke”, EU COST Program n. BM1406, the Ministry of Health, Italy (n. RF-2011-02348435), the Italian Ministry of Education, University and Research (n. RBAP11FXBC_001), and institutional funds from the University of Ferrara (FAR 2013).
References (63)
- et al.
Immunity, inflammation and cancer: a leading role for adenosine
Nat. Rev. Cancer
(2013) - et al.
P2X7 receptor-stimulation causes fever via PGE2 and IL-1beta release
FASEB J.
(2012) - et al.
P2X4R + microglia drive neuropathic pain
Nat. Neurosci.
(2012) - et al.
ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment
Cell Death Dis.
(2014) Physiology and pathophysiology of purinergic neurotransmission
Physiol. Rev.
(2007)Purinergic signalling: from discovery to current developments
Exp. Physiol.
(2014)- et al.
Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis
Nature
(2010) - et al.
Adenosine receptors as drug targets—what are the challenges?
Nat. Rev. Drug Discov.
(2013) - et al.
Spontaneous cell fusion in macrophage cultures expressing high levels of the P2Z/P2X7 receptor
J. Cell Biol.
(1997) - et al.
The ATP4- receptor of rat mast cells
Biochem. J.
(1980)