Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases
Wenjing Ren1,2, Patrizia Rubini1,2, Yong Tang1,2
1International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of TCM, Chengdu 610075, China.
Abstract:
Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophage-localized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1β (pro-IL-1β)-degrading caspase-1 to lead to IL-1β release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences.
Insights
Macrophages utilize P2X7 receptors (Rs) to regulate immune responses. Targeting these P2X7Rs on macrophages may offer therapeutic strategies for inflammatory diseases by preserving immune homeostasis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Macrophages are critical immune cells with diverse roles, existing as M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes.
- These cells originate from monocytes or reside in tissues like the liver, spleen, and lungs.
- Macrophages express P2X7 receptors (Rs), which are involved in cellular responses to extracellular ATP.
Purpose of the Study:
- To investigate the role of macrophage P2X7 receptors in immune regulation and inflammatory processes.
- To explore the molecular mechanisms underlying P2X7R activation and its downstream effects.
- To assess the therapeutic potential of targeting macrophage P2X7Rs for inflammatory diseases.
Main Methods:
- Analysis of P2X7 receptor (R) function in macrophages under varying ATP concentrations.
- Investigating the interaction of P2X7R with other membrane channels (e.g., P2X4R, TRPA1, pannexin-1, ANO6).
- Examining the co-activation of P2X7R with toll-like receptor 4 (TLR4) and its role in inflammasome (NLRP3) activation and IL-1β release.
Main Results:
- High extracellular ATP concentrations activate P2X7Rs, leading to cation fluxes and pore formation permeable to large molecules.
- P2X7R activation requires interaction with other membrane channels for full functional response.
- Co-activation of macrophage P2X7Rs and TLR4 is essential for NLRP3 inflammasome assembly and subsequent caspase-1 activation, driving IL-1β release.
- P2X7R signaling contributes to the upregulation of inflammatory mediators and pathways implicated in diseases like rheumatoid arthritis and sepsis.
Conclusions:
- Macrophage P2X7 receptors play a pivotal role in initiating inflammatory responses.
- The intricate interplay between P2X7R, TLR4, and inflammasome components is crucial for immune cell activation.
- Targeting macrophage P2X7Rs presents a promising therapeutic avenue for managing inflammatory conditions and maintaining immune homeostasis.
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