Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Basic Science Article
  • Published:

Implications of neonatal absence of innate immune mediated NFκB/AP1 signaling in the murine liver

Pediatric Research (2024)Cite this article

Abstract

Background

The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown.

Methods

Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes.

Results

We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis. This is associated with absent hepatic p65/NFκB signaling and impaired expression of anti-apoptotic target genes. Hepatic c-Jun/AP1 activity was attenuated in endotoxemic P3 mice, with resulting upregulation of pro-apoptotic factors.

Conclusions

These results demonstrate that developmental absence of innate immune p65/NFκB and c-Jun/AP1 signaling, and target gene expression is associated with apoptotic injury in neonatal mice. More work is needed to determine if this contributes to long-term hepatic dysfunction, and whether immunomodulatory approaches can prevent this injury.

Impact

  • Various aspects of developmental immaturity of the innate immune system may help explain the increased risk of infection in the neonatal period.

  • In adult models of inflammation and infection, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for a protective, pro-inflammatory transcriptome and regulation of apoptosis.

  • We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis associated with absent hepatic p65/NFκB signaling and c-Jun/AP1 activity.

  • We believe that these results may explain in part hepatic dysfunction with neonatal sepsis, and that there may be unrecognized developmental and long-term hepatic implications of early life exposure to systemic inflammatory stress.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Endotoxemia causes histopathologic evidence of liver injury in P3 mice.
Fig. 2: Endotoxemia causes hepatic apoptosis in P3 mice.
Fig. 3: Endotoxemia-induced hepatic p65/NFκB signaling is developmentally regulated.
Fig. 4: Endotoxemia-induced p65/NFκB signaling occurs in hepatocytes in adult mice.
Fig. 5: Endotoxemia-induced hepatic c-Jun/AP-1 signaling is developmentally regulated.
Fig. 6: Endotoxemia-induced expression of hepatic p65/NFκB and c-Jun/AP1 apoptotic related genes is developmentally-regulated.

Similar content being viewed by others

Data availability

All data, analytic methods and study materials will be made available to other researchers upon request.

References

  1. Fleischmann-Struzek, C. et al. The global burden of paediatric and neonatal sepsis: a systematic review. Lancet Respir. Med 6, 223–230 (2018).

    Article  PubMed  Google Scholar 

  2. Schlapbach, L. J. et al. Impact of sepsis on neurodevelopmental outcome in a Swiss national cohort of extremely premature infants. Pediatrics 128, e348–e357 (2011).

    Article  PubMed  Google Scholar 

  3. Kollmann, T. R., Kampmann, B., Mazmanian, S. K., Marchant, A. & Levy, O. Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny. Immunity 46, 350–363 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Sadeghi, K. et al. Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. J. Infect. Dis. 195, 296–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Roger, T. et al. High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates. Proc. Natl Acad. Sci. USA 113, E997–E1005 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Levy, O. & Wynn, J. L. A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 105, 136–141 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Henneke, P., Kierdorf, K., Hall, L. J., Sperandio, M. & Hornef, M. Perinatal development of innate immune topology. Elife 10, e67793 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yu, J. C. et al. Innate immunity of neonates and infants. Front Immunol. 9, 1759 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Strunk, T., Currie, A., Richmond, P., Simmer, K. & Burgner, D. Innate immunity in human newborn infants: prematurity means more than immaturity. J. Matern Fetal Neonatal Med 24, 25–31 (2011).

    Article  PubMed  Google Scholar 

  11. Zhou, Z., Xu, M. J. & Gao, B. Hepatocytes: a key cell type for innate immunity. Cell Mol. Immunol. 13, 301–315 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Yan, J., Li, S. & Li, S. The role of the liver in sepsis. Int Rev. Immunol. 33, 498–510 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Robinson, M. W., Harmon, C. & O’Farrelly, C. Liver immunology and its role in inflammation and homeostasis. Cell Mol. Immunol. 13, 267–276 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Racanelli, V. & Rehermann, B. The liver as an immunological organ. Hepatology 43, S54–S62 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Kubes, P. & Jenne, C. Immune responses in the liver. Annu Rev. Immunol. 36, 247–277 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Knolle, P. A. & Gerken, G. Local control of the immune response in the liver. Immunol. Rev. 174, 21–34 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14, 996–1006 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Heymann, F. & Tacke, F. Immunology in the liver–from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Gao, B., Jeong, W. I. & Tian, Z. Liver: an organ with predominant innate immunity. Hepatology 47, 729–736 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Strnad, P., Tacke, F., Koch, A. & Trautwein, C. Liver - guardian, modifier and target of sepsis. Nat. Rev. Gastroenterol. Hepatol. 14, 55–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Bode, J. G., Albrecht, U., Häussinger, D., Heinrich, P. C. & Schaper, F. Hepatic acute phase proteins–regulation by Il-6- and Il-1-type cytokines involving stat3 and its crosstalk with NF-κB-dependent signaling. Eur. J. Cell Biol. 91, 496–505 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Crispe, I. N. Hepatocytes as immunological agents. J. Immunol. 196, 17–21 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Gabay, C. & Kushner, I. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med 340, 448–454 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Quinton, L. J., Jones, M. R., Robson, B. E. & Mizgerd, J. P. Mechanisms of the hepatic acute-phase response during bacterial pneumonia. Infect. Immun. 77, 2417–2426 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Quinton, L. J. et al. Hepatocyte-specific mutation of both NF-kappaB rela and stat3 abrogates the acute phase response in mice. J. Clin. Invest 122, 1758–1763 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hilliard, K. L. et al. The lung-liver axis: a requirement for maximal innate immunity and hepatoprotection during pneumonia. Am. J. Respir. Cell Mol. Biol. 53, 378–390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lavon, I. et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. Nat. Med 6, 573–577 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Kim, Y. et al. NF-kappaB rela is required for hepatoprotection during pneumonia and sepsis. Infect. Immun. 87, e00132–19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kilpinen, S., Henttinen, T., Lahdenpohja, N., Hulkkonen, J. & Hurme, M. Signals leading to the activation of NF-kappaB transcription factor are stronger in neonatal than adult T lymphocytes. Scand. J. Immunol. 44, 85–88 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Vancurova, I., Bellani, P. & Davidson, D. Activation of nuclear factor-kappaB and its suppression by dexamethasone in polymorphonuclear leukocytes: newborn versus adult. Pediatr. Res 49, 257–262 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Wright, C. J., Zhuang, T., La, P., Yang, G. & Dennery, P. A. Hyperoxia-induced NF-kappaB activation occurs via a maturationally sensitive atypical pathway. Am. J. Physiol. Lung Cell Mol. Physiol. 296, L296–L306 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Yang, G., Abate, A., George, A. G., Weng, Y. H. & Dennery, P. A. Maturational differences in lung NF-kappaB activation and their role in tolerance to hyperoxia. J. Clin. Invest 114, 669–678 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Claud, E. C. et al. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc. Natl Acad. Sci. USA 101, 7404–7408 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. McKenna, S. et al. Endotoxemia induces IkappaBbeta/NF-kappaB-dependent endothelin-1 expression in hepatic macrophages. J. Immunol. 195, 3866–3879 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. McKenna, S. et al. Perinatal endotoxemia induces sustained hepatic Cox-2 expression through an NfkappaB-dependent mechanism. J. Innate Immun. 8, 386–399 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zarate, M. A., Nguyen, L. M., De Dios, R. K., Zheng, L. & Wright, C. J. Maturation of the acute hepatic TLR4/NF-kappaB mediated innate immune response Is P65 dependent in mice. Front Immunol. 11, 1892 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. McKenna, S. et al. Immunotolerant P50/NFkappaB signaling and attenuated hepatic IFNbeta expression increases neonatal sensitivity to endotoxemia. Front Immunol. 9, 2210 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wullaert, A., van Loo, G., Heyninck, K. & Beyaert, R. Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr. Rev. 28, 365–386 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Luedde, T. & Schwabe, R. F. NF-kappaB in the liver–linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 8, 108–118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Leist, M. et al. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-Alpha requires transcriptional arrest. J. Immunol. 153, 1778–1788 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Lehmann, V., Freudenberg, M. A. & Galanos, C. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J. Exp. Med 165, 657–663 (1987).

    Article  CAS  PubMed  Google Scholar 

  42. Nagaki, M. et al. Lethal hepatic apoptosis mediated by tumor necrosis factor receptor, unlike fas-mediated apoptosis, requires hepatocyte sensitization in mice. J. Hepatol. 31, 997–1005 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Geisler, F., Algul, H., Paxian, S. & Schmid, R. M. Genetic inactivation of Rela/P65 sensitizes adult mouse hepatocytes to TNF-induced apoptosis in vivo and in vitro. Gastroenterology 132, 2489–2503 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Xu, Y. et al. NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis. Am. J. Physiol. 275, C1058–C1066 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Alcamo, E. et al. Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for Nf-kappaB in leukocyte recruitment. J. Immunol. 167, 1592–1600 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Luedde, T. et al. Deletion of NEMO/Ikkgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Bellas, R. E., FitzGerald, M. J., Fausto, N. & Sonenshein, G. E. Inhibition of NF-kappa B activity induces apoptosis in murine hepatocytes. Am. J. Pathol. 151, 891–896 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Doi, T. S. et al. Absence of tumor necrosis factor rescues rela-deficient mice from embryonic lethality. Proc. Natl Acad. Sci. USA 96, 2994–2999 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rosenfeld, M. E., Prichard, L., Shiojiri, N. & Fausto, N. Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice. Am. J. Pathol. 156, 997–1007 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Iimuro, Y. et al. NfkappaB prevents apoptosis and liver dysfunction during liver regeneration. J. Clin. Invest 101, 802–811 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chaisson, M. L., Brooling, J. T., Ladiges, W., Tsai, S. & Fausto, N. Hepatocyte-specific inhibition of NF-kappaB leads to apoptosis after TNF treatment, but not after partial hepatectomy. J. Clin. Invest 110, 193–202 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bettermann, K. et al. Tak1 suppresses a nemo-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 17, 481–496 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Luedde, T. et al. Deletion of Ikk2 in hepatocytes does not sensitize these cells to Tnf-induced apoptosis but protects from ischemia/reperfusion injury. J. Clin. Invest 115, 849–859 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Maeda, S. et al. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19, 725–737 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Luedde, T. et al. Ikk1 and Ikk2 cooperate to maintain bile duct integrity in the liver. Proc. Natl Acad. Sci. USA 105, 9733–9738 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yang, G., Madan, A. & Dennery, P. A. Maturational differences in hyperoxic Ap-1 activation in rat lung. Am. J. Physiol. Lung Cell Mol. Physiol. 278, L393–L398 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Choi, A. M., Sylvester, S., Otterbein, L. & Holbrook, N. J. Molecular responses to hyperoxia in vivo: relationship to increased tolerance in aged rats. Am. J. Respir. Cell Mol. Biol. 13, 74–82 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Tong, L. et al. Attenuated transcriptional responses to oxidative stress in the aged rat brain. J. Neurosci. Res 70, 318–326 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Eferl, R. et al. Functions of c-Jun in liver and heart development. J. Cell Biol. 145, 1049–1061 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hilberg, F., Aguzzi, A., Howells, N. & Wagner, E. F. c-Jun is essential for normal mouse development and hepatogenesis. Nature 365, 179–181 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  61. Behrens, A. et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-Jun in the liver. EMBO J. 21, 1782–1790 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schreiber, M. et al. Control of cell cycle progression by c-Jun Is P53 dependent. Genes Dev. 13, 607–619 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eferl, R. et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of P53. Cell 112, 181–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Butler, B. et al. Developmentally regulated innate immune NF-kappaB signaling mediates Il-1alpha expression in the perinatal murine lung. Front Immunol. 10, 1555 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nguyen, L. et al. The hepatic innate immune response is lobe-specific in a murine model endotoxemia. Innate Immun. 25, 144–154 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lanaspa, M. A. et al. Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J. Clin. Invest 128, 2226–2238 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sherlock, L. G. et al. Apap-induced IkappaBbeta/NfkappaB signaling drives hepatic Il6 expression and associated sinusoidal dilation. Toxicol. Sci. 185, 158–169 (2022).

    Article  CAS  PubMed  Google Scholar 

  68. Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev. Immunol. 32, 659–702 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Hayden, M. S. & Ghosh, S. Signaling to NF-kappaB. Genes Dev. 18, 2195–2224 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Arvelo, M. B. et al. A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis. Hepatology 35, 535–543 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. & Baltimore, D. Embryonic lethality and liver degeneration in mice lacking the rela component of Nf-Kappa B. Nature 376, 167–170 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  72. Doi, T. S. et al. Rela-deficient lymphocytes: normal development of T cells and B Cells, impaired production of Iga and Igg1 and reduced proliferative responses. J. Exp. Med 185, 953–961 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li, Z. W. et al. The IKKbeta subunit of IkappaB kinase (IKK) Is essential for nuclear factor kappaB activation and prevention of apoptosis. J. Exp. Med 189, 1839–1845 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. & Verma, I. M. Severe liver degeneration in mice lacking the ikappaB kinase 2 gene. Science 284, 321–325 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  75. Makris, C. et al. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5, 969–979 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Tanaka, M. et al. Embryonic lethality, liver degeneration, and impaired NF-kappaB activation in ikk-beta-deficient mice. Immunity 10, 421–429 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Rudolph, D. et al. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev. 14, 854–862 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu, S. et al. Characterization of Rat Cd14 promoter and its regulation by transcription factors Ap1 and Sp family proteins in hepatocytes. Gene 250, 137–147 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Iida, A. et al. Hepatocyte nuclear factor-kappa beta (NF-kappaB) activation is protective but is decreased in the cholestatic liver with endotoxemia. Surgery 148, 477–489 (2010).

    Article  PubMed  Google Scholar 

  80. Hochhauser, E. et al. Bone marrow and nonbone marrow toll like receptor 4 regulate acute hepatic injury induced by endotoxemia. PLoS ONE 8, e73041 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Takamura, M. et al. An inhibitor of c-Jun Nh2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating Bh3-only proteins. Life Sci. 80, 1335–1344 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Ben Ari, Z. et al. Reduced hepatic injury in toll-like receptor 4-deficient mice following d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Cell Physiol. Biochem 29, 41–50 (2012).

    Article  ADS  PubMed  Google Scholar 

  83. Trusca, V. G., Fuior, E. V., Kardassis, D., Simionescu, M. & Gafencu, A. V. The opposite effect of c-Jun transcription factor on apolipoprotein E gene regulation in hepatocytes and macrophages. Int J. Mol. Sci. 20, 1471 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fischer, M. Census and evaluation of P53 target genes. Oncogene 36, 3943–3956 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nakano, K. & Vousden, K. H. Puma, a novel proapoptotic gene, is induced by P53. Mol. Cell 7, 683–P694 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Tan, S. et al. Fas/fasl mediates NF-kappaBp65/puma-modulated hepatocytes apoptosis via autophagy to drive liver fibrosis. Cell Death Dis. 12, 474 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cazanave, S. C. et al. Jnk1-dependent puma expression contributes to hepatocyte lipoapoptosis. J. Biol. Chem. 284, 26591–26602 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Alcorn, J. M., Fierer, J. & Chojkier, M. The acute-phase response protects mice from d-galactosamine sensitization to endotoxin and tumor necrosis factor-alpha. Hepatology 15, 122–129 (1992).

    Article  CAS  PubMed  Google Scholar 

  89. Libert, C., Van Bladel, S., Brouckaert, P., Shaw, A. & Fiers, W. Involvement of the liver, but not of Il-6, in Il-1-induced desensitization to the lethal effects of tumor necrosis factor. J. Immunol. 146, 2625–2632 (1991).

    Article  CAS  PubMed  Google Scholar 

  90. de la Coste, A. et al. Differential protective effects of Bcl-Xl and Bcl-2 on apoptotic liver injury in transgenic mice. Am. J. Physiol. 277, G702–G708 (1999).

    PubMed  Google Scholar 

  91. Nagaki, M. et al. Tumor necrosis factor alpha prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not fas-mediated apoptosis: role of nuclear factor-kappaB. Hepatology 32, 1272–1279 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Jia, F. et al. Nod1 agonist protects against lipopolysaccharide and d-galactosamine-induced fatal hepatitis through the upregulation of A20 expression in hepatocytes. Front Immunol. 12, 603192 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee, E. G. et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in a20-deficient mice. Science 289, 2350–2354 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  94. Catrysse, L. et al. A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death. Cell Death Dis. 7, e2250 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Park, J. M. et al. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis–CREB and NF-kappaB as key regulators. Immunity 23, 319–329 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Okada, S., Zhang, H., Hatano, M. & Tokuhisa, T. A physiologic role of Bcl-Xl induced in activated macrophages. J. Immunol. 160, 2590–2596 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Yabal, M. et al. Xiap restricts tnf- and Rip3-dependent cell death and inflammasome activation. Cell Rep. 7, 1796–1808 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Conte, D. et al. Inhibitor of apoptosis protein ciap2 is essential for lipopolysaccharide-induced macrophage survival. Mol. Cell Biol. 26, 699–708 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by NIH grant R01HD107700 to CJW.

Author information

Authors and Affiliations

  1. Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Maya R. Grayck, William C. McCarthy, Mack Solar, Natarajan Balasubramaniyan, Lijun Zheng & Clyde J. Wright

  2. Dept of Pathology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA

    David J. Orlicky

Authors
  1. Maya R. Grayck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William C. McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mack Solar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natarajan Balasubramaniyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lijun Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David J. Orlicky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Clyde J. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CJW conception and design of research; MRG, WCM, MS, NB, LZ performed experiments; MRG, WCM, NB, DJO analyzed data; MRG, DJO, CJW interpreted results of experiments; CJW drafted the manuscript; MRG, WCM prepared figures; MRG, WCM, MS, NB, LZ, CJW edited and revised manuscript; CJW approved final version of manuscript.

Corresponding author

Correspondence to Clyde J. Wright.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

All procedures were approved by the University of Colorado Institutional Animal Care and Use Committee (00457) and performed in compliance with the American Association for Accreditation for Laboratory Animal Care at the Perinatal Research Center at the University of Colorado School of Medicine (Aurora, CO).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grayck, M.R., McCarthy, W.C., Solar, M. et al. Implications of neonatal absence of innate immune mediated NFκB/AP1 signaling in the murine liver. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03071-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-024-03071-0

Search

Advanced search

Quick links