Purinergic Signaling Via P2X Receptors and Mechanisms of Unregulated ATP Release in the Outer Retina and Age-related Macular Degeneration

Overview

Journal Front Neurosci

Date 2023 Jul 27

PMID 37496736

Authors

Haydn Molcak

Kailun Jiang

Christopher J Campbell

Joanne A Matsubara

Affiliations

Soon will be listed here.

Abstract

Age-related macular degeneration (AMD) is a chronic and progressive inflammatory disease of the retina characterized by photoceptor loss and significant central visual impairment due to either choroidal neovascularization or geographic atrophy. The pathophysiology of AMD is complex and multifactorial, driven by a combination of modifiable and non-modifiable risk factors, molecular mechanisms, and cellular processes that contribute to overall disease onset, severity, and progression. Unfortunately, due to the structural, cellular, and pathophysiologic complexity, therapeutic discovery is challenging. While purinergic signaling has been investigated for its role in the development and treatment of ocular pathologies including AMD, the potential crosstalk between known contributors to AMD, such as the complement cascade and inflammasome activation, and other biological systems, such as purinergic signaling, have not been fully characterized. In this review, we explore the interactions between purinergic signaling, ATP release, and known contributors to AMD pathogenesis including complement dysregulation and inflammasome activation. We begin by identifying what is known about purinergic receptors in cell populations of the outer retina and potential sources of extracellular ATP required to trigger purinergic receptor activation. Next, we examine evidence in the literature that the purinergic system accelerates AMD pathogenesis leading to apoptotic and pyroptotic cell death in retinal cells. To fully understand the potential role that purinergic signaling plays in AMD, more research is needed surrounding the expression, distribution, functions, and interactions of purinergic receptors within cells of the outer retina as well as potential crosstalk with other systems. By determining how these processes are affected in the context of purinergic signaling, it will improve our understanding of the mechanisms that drive AMD pathogenesis which is critical in developing treatment strategies that prevent or slow progression of the disease.

References

Medina C, Mehrotra P, Arandjelovic S, Perry J, Guo Y, Morioka S . Metabolites released from apoptotic cells act as tissue messengers. Nature. 2020; 580(7801):130-135. PMC: 7217709. DOI: 10.1038/s41586-020-2121-3. View

Bohana-Kashtan O, Ziporen L, Donin N, Kraus S, Fishelson Z . Cell signals transduced by complement. Mol Immunol. 2004; 41(6-7):583-97. DOI: 10.1016/j.molimm.2004.04.007. View

Thurman J, Renner B, Kunchithapautham K, Ferreira V, Pangburn M, Ablonczy Z . Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem. 2009; 284(25):16939-16947. PMC: 2719331. DOI: 10.1074/jbc.M808166200. View

Lavalette S, Raoul W, Houssier M, Camelo S, Levy O, Calippe B . Interleukin-1β inhibition prevents choroidal neovascularization and does not exacerbate photoreceptor degeneration. Am J Pathol. 2011; 178(5):2416-23. PMC: 3081145. DOI: 10.1016/j.ajpath.2011.01.013. View

Gu B, Baird P, Vessey K, Skarratt K, Fletcher E, Fuller S . A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of age-related macular degeneration. FASEB J. 2013; 27(4):1479-87. DOI: 10.1096/fj.12-215368. View

Adinolfi E, Giuliani A, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F . The P2X7 receptor: A main player in inflammation. Biochem Pharmacol. 2017; 151:234-244. DOI: 10.1016/j.bcp.2017.12.021. View

Broz P, Pelegrin P, Shao F . The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2019; 20(3):143-157. DOI: 10.1038/s41577-019-0228-2. View

Di Virgilio F, Sarti A, Coutinho-Silva R . Purinergic signaling, DAMPs, and inflammation. Am J Physiol Cell Physiol. 2020; 318(5):C832-C835. DOI: 10.1152/ajpcell.00053.2020. View

Wareham K, Seward E . P2X7 receptors induce degranulation in human mast cells. Purinergic Signal. 2016; 12(2):235-46. PMC: 4854833. DOI: 10.1007/s11302-016-9497-4. View

10.

Sakaki H, Tsukimoto M, Harada H, Moriyama Y, Kojima S . Autocrine regulation of macrophage activation via exocytosis of ATP and activation of P2Y11 receptor. PLoS One. 2013; 8(4):e59778. PMC: 3618444. DOI: 10.1371/journal.pone.0059778. View

11.

Luibl V, Isas J, Kayed R, Glabe C, Langen R, Chen J . Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J Clin Invest. 2006; 116(2):378-85. PMC: 1359048. DOI: 10.1172/JCI25843. View

12.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

13.

Jacobson K, Civan M . Ocular Purine Receptors as Drug Targets in the Eye. J Ocul Pharmacol Ther. 2016; 32(8):534-547. PMC: 5069731. DOI: 10.1089/jop.2016.0090. View

14.

Merle N, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina L . Complement System Part II: Role in Immunity. Front Immunol. 2015; 6:257. PMC: 4443744. DOI: 10.3389/fimmu.2015.00257. View

15.

Fowler B, Gelfand B, Kim Y, Kerur N, Tarallo V, Hirano Y . Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science. 2014; 346(6212):1000-3. PMC: 4274127. DOI: 10.1126/science.1261754. View

16.

Jacobson K, Delicado E, Gachet C, Kennedy C, von Kugelgen I, Li B . Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol. 2020; 177(11):2413-2433. PMC: 7205808. DOI: 10.1111/bph.15005. View

17.

Kerur N, Hirano Y, Tarallo V, Fowler B, Bastos-Carvalho A, Yasuma T . TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest Ophthalmol Vis Sci. 2013; 54(12):7395-401. PMC: 3825570. DOI: 10.1167/iovs.13-12500. View

18.

Narendran S, Pereira F, Yerramothu P, Apicella I, Wang S, Ambati K . Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration. Signal Transduct Target Ther. 2021; 6(1):149. PMC: 8044134. DOI: 10.1038/s41392-021-00537-z. View

19.

Illes P, Khan T, Rubini P . Neuronal P2X7 Receptors Revisited: Do They Really Exist?. J Neurosci. 2017; 37(30):7049-7062. PMC: 6705732. DOI: 10.1523/JNEUROSCI.3103-16.2017. View

20.

Kumar-Singh R . The role of complement membrane attack complex in dry and wet AMD - From hypothesis to clinical trials. Exp Eye Res. 2019; 184:266-277. DOI: 10.1016/j.exer.2019.05.006. View