Purinergic signalling in autoimmunity: A role for the P2X7R in systemic lupus erythematosus?

Abstract

Purinergic signalling plays a crucial role in immunity and autoimmunity. Among purinergic receptors, the P2X7 receptor (P2X7R) has an undisputed role as it is expressed to high level by immune cells, triggers cytokine release and modulates immune cell differentiation. In this review, we focus on evidence supporting a possible role of the P2X7R in the pathogenesis of systemic lupus erythematosus (SLE).

Keywords: Extracellular ATP; Interleukin-1β; NLRP3 inflammasome; P2X7R; Systemic lupus erythematosus.

Fig. 1

Suggested central role of P2X7R and NLRP3 inflammasome in the pathways leading to autoimmunity and tissue damage in SLE. The different types of cell death can generate molecules that contribute to inflammation and tissue damage in SLE. NETosis, which is dependent on NLRP3 inflammasome activation, produces NETs and the cathelicidin LL-37. Pyroptosis, also dependent on NLRP3 inflammasome activation, causes HMGB1 and DNA release. Finally, defective apoptosis is responsible for nucleic acid release. NETs/LL-37 activate the P2X7R leading to production and release of IL-1β and IL-18, thus promoting inflammation. IL-1β is in turn responsible of increased NETs formation from neutrophils and LDGs. Interleukin-18 works in combination with IL-6 and IL-23 to reduce T-reg and MDSC activity, to enhance Th17 activity and inflammation. NETs are also responsible for EC damage with consequent release of immune stimulatory molecules and tolerance breaking. HMGB1 interaction with TLR4 contributes to inflammation through activation of NF-kB and release of the inflammatory cytokines TNF-α and IL-6. TNF-α is responsible for keratinocyte apoptosis, a process that generates autoantigens. The alarmin HMGB1, is released upon P2X7R/NLRP3 activation and in cooperation with DNA contributes to ANA formation. Nucleic acids are responsible for production of ANAs that participate in formation of ICs. ICs on one hand, interact with RAGEs on endothelial cells, thus causing vasculopathy, whereas on the other stimulate pDCs to produce IFN-α. Abbreviations: NETs: neutrophil extracellular trap-associated proteins; HMGB1: high molecular group box-1; ANA: anti-nuclear antibodies; MDSC: myeloid derived suppressor cells; pDCs: plasmacytoid dendritic cells; K: keratinocytes; LDGs: low-density granulocytes; TLR4: Toll-like receptor 4; ICs: immune complexes; RAGEs: receptor for advanced glycation end products; NLRP3: NOD-like receptor family pyrin domain-containing 3.