Involvement of the P2X7-NLRP3 axis in leukemic cell proliferation and death.

Abstract

Lymphocyte growth and differentiation are modulated by extracellular nucleotides and P2 receptors. We previously showed that the P2X7 receptor (P2X7R or P2RX7) is overexpressed in circulating lymphocytes from chronic lymphocytic leukemia (CLL) patients. In the present study we investigated the P2X7R/NLRP3 inflammasome axis in lymphocytes from a cohort of 23 CLL patients. P2X7R, ASC and NLRP3 were investigated by Western blot, PCR and transfection techniques. P2X7R was overexpressed and correlated with chromosome 12 trisomy in CLL patients. ASC mRNA and protein were also overexpressed. On the contrary, NLRP3 was dramatically down-modulated in CLL lymphocytes relative to lymphocytes from healthy donors. To further investigate the correlation between P2X7R, NLRP3 and cell growth, NLRP3 was silenced in THP-1 cells, a leukemic cell line that natively expresses both NLRP3 and P2X7R. NLRP3 silencing enhanced P2X7R expression and promoted growth. On the contrary, NLRP3 overexpression caused accelerated apoptosis. The P2X7R was also up-modulated in hematopoietic cells from NLRP3-KO mice. In conclusion, we show that NLRP3 down-modulation stimulates P2X7R expression and promotes growth, while NLRP3 overexpression inhibits cell proliferation and stimulates apoptosis. These findings suggest that NLRP3 is a negative regulator of growth and point to a role of the P2X7R/NLRP3 axis in CLL.

• Authors: Erica Salaro, Alessia Rambaldi, Simonetta Falzoni, Francesca Saveria Amoroso, Alessia Franceschini, Alba Clara Sarti, Massimo Bonora, Francesco Cavazzini, Gian Matteo Rigolin, Maria Ciccone, Valentina Audrito, Silvia Deaglio, Pablo Pelegrin, Paolo Pinton, Antonio Cuneo, Francesco Di Virgilio
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 26280 (05 25 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27221966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CARD Signaling Adaptor Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Nlrp3 protein, mouse
• P2RX7 protein, human
• PYCARD protein, human
• RNA, Messenger
• RNA, Neoplasm
• RNA, Small Interfering
• Receptors, Purinergic P2X7

Topics

• Aged
• Aged, 80 and over
• Animals
• Apoptosis
• CARD Signaling Adaptor Proteins (metabolism)
• Cell Proliferation
• Female
• HEK293 Cells
• Humans
• Inflammasomes (immunology, metabolism)
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, deficiency, genetics, metabolism)
• RNA Interference
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Receptors, Purinergic P2X7 (metabolism)
• THP-1 Cells