Persistent DNA Damage-induced NLRP12 Improves Hematopoietic Stem Cell Function

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2020 May 22

PMID 32434992

Citations 7

Authors

Qiqi Lin

Limei Wu

Zhilin Ma

Fabliha Ahmed Chowdhury

Habibul Hasan Mazumder

Wei Du

Affiliations

Soon will be listed here.

Abstract

NOD-like receptor 12 (NLRP12) is a member of the nucleotide-binding domain and leucine-rich repeat containing receptor inflammasome family that plays a central role in innate immunity. We previously showed that DNA damage upregulated NLRP12 in hematopoietic stem cells (HSCs) of mice deficient in the DNA repair gene Fanca. However, the role of NLRP12 in HSC maintenance is not known. Here, we show that persistent DNA damage-induced NLRP12 improves HSC function in both mouse and human models of DNA repair deficiency and aging. Specifically, treatment of Fanca-/- mice with the DNA cross-linker mitomycin C or ionizing radiation induces NLRP12 upregulation in phenotypic HSCs. NLRP12 expression is specifically induced by persistent DNA damage. Functionally, knockdown of NLRP12 exacerbates the repopulation defect of Fanca-/- HSCs. Persistent DNA damage-induced NLRP12 was also observed in the HSCs from aged mice, and depletion of NLRP12 in these aged HSCs compromised their self-renewal and hematopoietic recovery. Consistently, overexpression of NLRP12 substantially improved the long-term repopulating function of Fanca-/- and aged HSCs. Finally, persistent DNA damage-induced NLRP12 maintains the function of HSCs from patients with FA or aged donors. These results reveal a potentially novel role of NLRP12 in HSC maintenance and suggest that NLRP12 targeting has therapeutic potential in DNA repair disorders and aging.

Citing Articles

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References

Jacobs K, Misri S, Meyer B, Raj S, Zobel C, Sleckman B . Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses. Mol Biol Cell. 2016; 27(8):1332-45. PMC: 4831886. DOI: 10.1091/mbc.E16-01-0017. View

Du W, Amarachintha S, Wilson A, Pang Q . The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion. Leukemia. 2016; 31(2):423-433. PMC: 7163296. DOI: 10.1038/leu.2016.242. View

Rossi D, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman I . Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007; 447(7145):725-9. DOI: 10.1038/nature05862. View

Zaki M, Vogel P, Malireddi R, Body-Malapel M, Anand P, Bertin J . The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell. 2011; 20(5):649-60. PMC: 3761879. DOI: 10.1016/j.ccr.2011.10.022. View

Dewan M, Terashima K, Taruishi M, Hasegawa H, Ito M, Tanaka Y . Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB. J Virol. 2003; 77(9):5286-94. PMC: 153944. DOI: 10.1128/jvi.77.9.5286-5294.2003. View

Zhang Q, Marquez-Loza L, Eaton L, Duncan A, Goldman D, Anur P . Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol. Blood. 2010; 116(24):5140-8. PMC: 3012535. DOI: 10.1182/blood-2010-04-278226. View

Park J, Virts E, Jankowska A, Wiek C, Othman M, Chakraborty S . Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. J Med Genet. 2016; 53(10):672-680. PMC: 5035190. DOI: 10.1136/jmedgenet-2016-103847. View

Hodskinson M, Silhan J, Crossan G, Garaycoechea J, Mukherjee S, Johnson C . Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol Cell. 2014; 54(3):472-84. PMC: 4017094. DOI: 10.1016/j.molcel.2014.03.014. 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

10.

Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A . Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013; 92(5):800-6. PMC: 3644630. DOI: 10.1016/j.ajhg.2013.04.002. View

11.

Celeste A, Difilippantonio S, Difilippantonio M, Fernandez-Capetillo O, Pilch D, Sedelnikova O . H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell. 2003; 114(3):371-383. PMC: 4737479. DOI: 10.1016/s0092-8674(03)00567-1. View

12.

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

13.

Carreau M, Gan O, Liu L, Doedens M, McKerlie C, Dick J . Bone marrow failure in the Fanconi anemia group C mouse model after DNA damage. Blood. 1998; 91(8):2737-44. View

14.

Virts E, Jankowska A, MacKay C, Glaas M, Wiek C, Kelich S . AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. Hum Mol Genet. 2015; 24(18):5093-108. PMC: 4550815. DOI: 10.1093/hmg/ddv227. View

15.

Wunderlich M, Chou F, Link K, Mizukawa B, Perry R, Carroll M . AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010; 24(10):1785-8. PMC: 5439963. DOI: 10.1038/leu.2010.158. View

16.

Himburg H, Termini C, Schlussel L, Kan J, Li M, Zhao L . Distinct Bone Marrow Sources of Pleiotrophin Control Hematopoietic Stem Cell Maintenance and Regeneration. Cell Stem Cell. 2018; 23(3):370-381.e5. PMC: 6482945. DOI: 10.1016/j.stem.2018.07.003. View

17.

Prasher J, Lalai A, Heijmans-Antonissen C, Ploemacher R, Hoeijmakers J, Touw I . Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1-/- mice. EMBO J. 2005; 24(4):861-71. PMC: 549615. DOI: 10.1038/sj.emboj.7600542. View

18.

Li T, Zhou Z, Ju Z, Wang Z . DNA Damage Response in Hematopoietic Stem Cell Ageing. Genomics Proteomics Bioinformatics. 2016; 14(3):147-154. PMC: 4936660. DOI: 10.1016/j.gpb.2016.04.002. View

19.

Santivasi W, Xia F . Ionizing radiation-induced DNA damage, response, and repair. Antioxid Redox Signal. 2013; 21(2):251-9. DOI: 10.1089/ars.2013.5668. View

20.

Rossi D, Jamieson C, Weissman I . Stems cells and the pathways to aging and cancer. Cell. 2008; 132(4):681-96. DOI: 10.1016/j.cell.2008.01.036. View