NLRP12-PANoptosome Activates PANoptosis and Pathology in Response to Heme and PAMPs

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Jun 2

PMID 37267949

Authors

Balamurugan Sundaram

Nagakannan Pandian

Raghvendra Mall

Yaqiu Wang

Roman Sarkar

Hee Jin Kim

R K Subbarao Malireddi

Rajendra Karki

Laura J Janke

Peter Vogel

Thirumala-Devi Kanneganti

Affiliations

Soon will be listed here.

Abstract

Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1β and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.

Citing Articles

Heme Unleashed: NLRP12 Orchestrates PANoptosis in a Symphony of Cell Fate.

Navuluri N, Yata V, Dachani S, Rachakonda K, Kolliputi N Cell Biochem Biophys. 2025; .

PMID: 40055236 DOI: 10.1007/s12013-025-01712-7.

New insights into pulmonary arterial hypertension: interaction between PANoptosis and perivascular inflammatory responses.

Su X, Sun Y, Dai A Apoptosis. 2025; .

PMID: 39979525 DOI: 10.1007/s10495-025-02086-0.

Methamphetamine-mediated astrocytic pyroptosis and neuroinflammation involves miR-152-NLRP6 inflammasome signaling axis.

Oladapo A, Kannan M, Deshetty U, Singh S, Buch S, Periyasamy P Redox Biol. 2025; 80:103517.

PMID: 39879739 PMC: 11810843. DOI: 10.1016/j.redox.2025.103517.

ZBP1-mediated PANoptosis is a crucial lethal form in diverse keratinocyte death modalities in UVB-induced skin injury.

Bi X, Guo Y, Hu M, Chen Y, Lian N, Chen S Cell Death Dis. 2025; 16(1):44.

PMID: 39863598 PMC: 11762280. DOI: 10.1038/s41419-025-07351-3.

PANoptosis in Bacterial Infections: A Double-Edged Sword Balancing Host Immunity and Pathogenesis.

He X, Jiang X, Guo J, Sun H, Yang J Pathogens. 2025; 14(1).

PMID: 39861004 PMC: 11768250. DOI: 10.3390/pathogens14010043.

References

Borghini S, Tassi S, Chiesa S, Caroli F, Carta S, Caorsi R . Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 2011; 63(3):830-9. PMC: 3112487. DOI: 10.1002/art.30170. View

Kayagaki N, Stowe I, Lee B, ORourke K, Anderson K, Warming S . Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015; 526(7575):666-71. DOI: 10.1038/nature15541. View

Taabazuing C, Okondo M, Bachovchin D . Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages. Cell Chem Biol. 2017; 24(4):507-514.e4. PMC: 5467448. DOI: 10.1016/j.chembiol.2017.03.009. View

Chen K, Demarco B, Heilig R, Shkarina K, Boettcher A, Farady C . Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly. EMBO J. 2019; 38(10). PMC: 6517827. DOI: 10.15252/embj.2019101638. View

Lagresle-Peyrou C, Lefrere F, Magrin E, Ribeil J, Romano O, Weber L . Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica. 2018; 103(5):778-786. PMC: 5927997. DOI: 10.3324/haematol.2017.184788. View

Ataide M, Andrade W, Zamboni D, Wang D, Souza M, Franklin B . Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog. 2014; 10(1):e1003885. PMC: 3894209. DOI: 10.1371/journal.ppat.1003885. View

Man S, Karki R, Sasai M, Place D, Kesavardhana S, Temirov J . IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes. Cell. 2016; 167(2):382-396.e17. PMC: 5074697. DOI: 10.1016/j.cell.2016.09.012. View

Brito M, Baro B, Raiol T, Ayllon-Hermida A, Safe I, Deroost K . Morphological and Transcriptional Changes in Human Bone Marrow During Natural Plasmodium vivax Malaria Infections. J Infect Dis. 2020; 225(7):1274-1283. PMC: 8974851. DOI: 10.1093/infdis/jiaa177. View

Vermeulen Windsant I, Snoeijs M, Hanssen S, Altintas S, H Heijmans J, Koeppel T . Hemolysis is associated with acute kidney injury during major aortic surgery. Kidney Int. 2010; 77(10):913-20. DOI: 10.1038/ki.2010.24. View

10.

Vladimer G, Weng D, Paquette S, Vanaja S, Rathinam V, Aune M . The NLRP12 inflammasome recognizes Yersinia pestis. Immunity. 2012; 37(1):96-107. PMC: 3753114. DOI: 10.1016/j.immuni.2012.07.006. View

11.

Lukens J, Gurung P, Shaw P, Barr M, Zaki M, Brown S . The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells. Immunity. 2015; 42(4):654-64. PMC: 4412374. DOI: 10.1016/j.immuni.2015.03.006. View

12.

Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R . Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci U S A. 2009; 106(37):15837-42. PMC: 2728109. DOI: 10.1073/pnas.0903419106. View

13.

Lee S, Karki R, Wang Y, Nguyen L, Kalathur R, Kanneganti T . AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence. Nature. 2021; 597(7876):415-419. PMC: 8603942. DOI: 10.1038/s41586-021-03875-8. View

14.

Xu H, Shi J, Gao H, Liu Y, Yang Z, Shao F . The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin. EMBO J. 2019; 38(13):e101996. PMC: 6600268. DOI: 10.15252/embj.2019101996. View

15.

Wang Y, Gao W, Shi X, Ding J, Liu W, He H . Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017; 547(7661):99-103. DOI: 10.1038/nature22393. View

16.

Hollingsworth L, Sharif H, Griswold A, Fontana P, Mintseris J, Dagbay K . DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature. 2021; 592(7856):778-783. PMC: 8299537. DOI: 10.1038/s41586-021-03350-4. View

17.

Neogi U, Elaldi N, Appelberg S, Ambikan A, Kennedy E, Dowall S . Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target. Elife. 2022; 11. PMC: 9018070. DOI: 10.7554/eLife.76071. View

18.

Gai K, Okondo M, Rao S, Chui A, Ball D, Johnson D . DPP8/9 inhibitors are universal activators of functional NLRP1 alleles. Cell Death Dis. 2019; 10(8):587. PMC: 6683174. DOI: 10.1038/s41419-019-1817-5. View

19.

Karki R, Lee E, Place D, Samir P, Mavuluri J, Sharma B . IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation. Cell. 2018; 173(4):920-933.e13. PMC: 5935577. DOI: 10.1016/j.cell.2018.02.055. View

20.

AbouYabis A, Bell G . Hemolytic Anemia Complicating COVID-19 Infection. J Hematol. 2021; 10(5):221-227. PMC: 8577589. DOI: 10.14740/jh906. View