Abstract
Macrophages are unique innate immune cells that play an integral role in the defense of the host by virtue of their ability to recognize, engulf, and kill pathogens while sending out danger signals via cytokines to recruit and activate inflammatory cells. It is becoming increasingly clear that purinergic signaling events are essential components of the macrophage response to pathogen challenges and disorders such as sepsis may be, at least in part, regulated by these important sensors. The activation of the P2X7 receptor is a powerful event in the regulation of the caspase-1 inflammasome. We provide evidence that the inflammasome activation requires “priming” of macrophages prior to ATP activation of the P2X7R. Inhibition of the inflammasome activation by the tyrosine kinase inhibitor, AG126, suggests regulation by phosphorylation. Finally, the P2X7R may also be activated by other elements of the host response such as the antimicrobial peptide LL-37, which adds a new, physiologically relevant agonist to the P2X7R pathway. Therapeutic approaches to inflammation and sepsis will certainly be enhanced by an increased understanding of how purinergic receptors modulate the inflammasomes.
Similar content being viewed by others
References
Murphy PA, Simon PL, Willoughby WF (1980) Endogenous pyrogens made by rabbit peritoneal exudative cells are identical with lymphocyte-activating factors made by rabbit alveolar macrophages. J Immunol 124:2498–2501
Rosenwasser LJ, Dinarello CA (1981) Ability of human leukocyte pyrogen to enhance phytohemagglutinin induced murine thymocyte proliferation. Cell Immunol 63:134–142
Gu BJ, Zhang WY, Bendall LJ, Chessell IP, Buell GN, Wiley JS (2000) Expression of P2X(7) purinoceptors on human lymphocytes and monocytes: evidence for nonfunctional P2X(7) receptors. Am J Physiol Cell Physiol 279:C1189–C1197
Gudipaty L, Humphreys BD, Buell G, Dubyak GR (2001) Regulation of P2X(7) nucleotide receptor function in human monocytes by extracellular ions and receptor density. Am J Physiol Cell Physiol 280:C943–C953
Mehta VB, Hart J, Wewers MD (2001) ATP-stimulated release of interleukin (IL)-1b and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. J Biol Chem 276:3820–3826
Buell G, Chessell IP, Michel AD, Collo G, Salazzo M, Herren S, Gretener D, Grahames C, Kaur R, Kosco-Vilbois MH, Humphrey PP (1998) Blockade of human P2X7 receptor function with a monoclonal antibody. Blood 92:3521–3528
Aga M, Johnson CJ, Hart AP, Guadarrama AG, Suresh M, Svaren J, Bertics PJ, Darien BJ (2002) Modulation of monocyte signaling and pore formation in response to agonists of the nucleotide receptor P2X(7). J Leukoc Biol 72:222–232
Hogquist KA, Unanue ER, Chaplin DD (1991) Release of IL-1 from mononuclear phagocytes. J Immunol 147:2181–2186
Perregaux D, Gabel CA (1994) Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J Biol Chem 269:15195–15203
Ferrari D, Chiozzi P, Falzoni S, Dal Susino M, Melchiorri L, Baricordi OR, Di Virgilio F (1997) Extracellular ATP triggers IL-1b release by activating the purinergic P2Z receptor of human macrophages. J Immunol 159:1451–1458
Griffiths RJ, Stam EJ, Downs JT, Otterness IG (1995) ATP induces the release of IL-1 from LPS-primed cells in vivo. J Immunol 154:2821–2828
Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MSS (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275:206–209
Kahlenberg JM, Dubyak GR (2004) Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol 286:C1100–C1108
Novogrodsky A, Vanichkin A, Patya M, Gazit A, Osherov N, Levitzki A (1994) Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors. Science 264:1319–1322
Cuzzocrea S, McDonald MC, Mazzon E, Siriwardena D, Calabro G, Britti D, Mazzullo G, De Sarro A, Caputi AP, Thiemermann C (2000) The tyrosine kinase inhibitor tyrphostin AG126 reduces the development of acute and chronic inflammation. Am J Pathol 157:145–158
Sarkar A, Hall MW, Exline M, Hart J, Knatz N, Gatson N, Wewers MD (2006) Caspase-1 regulates Escherichia coli sepsis and splenic B cell apoptosis independently of interleukin-1beta and interleukin-18. Am J Respir Crit Care Med 174:1003–1010
Shemon AN, Sluyter R, Stokes L, Manley PW, Wiley JS (2008) Inhibition of the human P2X7 receptor by a novel protein tyrosine kinase antagonist. Biochem Biophys Res Commun 365:515–520
Kim M, Jiang LH, Wilson HL, North RA, Surprenant A (2001) Proteomic and functional evidence for a P2X7 receptor signalling complex. EMBO J 20:6347–6358
Ayala JM, Yamin T-T, Egger LA, Chin J, Kostura MJ, Miller DK (1994) IL-1beta-converting enzyme is present in monocytic cells as an inactive 45-kDa precursor. J Immunol 153:2592–2599
Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER (1982) Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis 126:332–337
Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS (1997) ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 7:433–444
van Furth R, Cohn ZA (1968) The origin and kinetics of mononuclear phagocytes. J Exp Med 128:415–433
van Furth R (1985) Monocyte production during inflammation. Comp Immunol Microbiol Infect Dis 8:205–211
Fahy RJ, Doseff AI, Wewers MD (1999) Spontaneous human monocyte apoptosis utilizes a caspase-3 dependent pathway which is blocked by endotoxin and is independent of caspase-1. J Immunol 163:1755–1762
Wewers MD, Herzyk DJ (1989) Alveolar macrophages differ from blood monocytes in human IL-1 beta release. Quantitation by enzyme-linked immunoassay. J Immunol 143:1635–1641
Wewers MD, Rennard SI, Hance AJ, Bitterman PB, Crystal RG (1984) Normal human alveolar macrophages obtained by bronchoalveolar lavage have a limited capacity to release interleukin-1. J Clin Invest 74:2208–2218
Laliberte RE, Eggler J, Gabel CA (1999) ATP treatment of human monocytes promotes caspase-1 maturation and externalization. J Biol Chem 274:36944–36951
Beigi R, Kobatake E, Aizawa M, Dubyak GR (1999) Detection of local ATP release from activated platelets using cell surface-attached firefly luciferase. Am J Physiol Cell Physiol 276:C267–C278
Sperlagh B, Hasko G, Nemeth Z, Vizi ES (1998) ATP released by LPS increases nitric oxide production in raw 264.7 macrophage cell line via P2Z/P2X7 receptors. Neurochem Int 33:209–215
Elssner A, Duncan M, Gavrilin M, Wewers MD (2004) A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J Immunol 172:4987–4994
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232
Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082
Perregaux D, Barberia J, Lanzetti AJ, Geoghegan KF, Carty TJ, Gabel CA (1992) IL-1 beta maturation: evidence that mature cytokine formation can be induced specifically by nigericin. J Immunol 149:1294–1303
Pelegrin P, Surprenant A (2007) Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. J Biol Chem 282:2386–2394
Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH, Franchi L, Vandenabeele P, Núñez G (2007) Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26:433–443
Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL (2001) Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291:1544–1547
Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, Flavell RA (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–734
Perregaux DG, Bhavsar K, Contillo L, Shi J, Gabel CA (2002) Antimicrobial peptides initiate IL-1 beta posttranslational processing: a novel role beyond innate immunity. J Immunol 168:3024–3032
Fahy RJ, Wewers MD (2005) Pulmonary defense and the human cathelicidin hCAP-18/LL-37. Immunol Res 31:75–89
Bals R, Wang X, Zasloff M, Wilson JM (1998) The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci USA 95:9541–9546
Johansson J, Gudmundsson GH, Rottenberg ME, Berndt KD, Agerberth B (1998) Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J Biol Chem 273:3718–3724
Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Heumann D (2001) Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. J Immunol 167:3329–3338
Acknowledgments
Timothy Eubank, Ph.D. for graphic design support.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wewers, M.D., Sarkar, A. P2X7 receptor and macrophage function. Purinergic Signalling 5, 189–195 (2009). https://doi.org/10.1007/s11302-009-9131-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11302-009-9131-9