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Interaction of aging with lipoxygenase deficiency initiates hypersplenism, cardiac dysfunction, and profound leukocyte directed non-resolving inflammation

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Abstract

In the process of physiological cardiac repair, splenic leukocyte-activated lipoxygenases (LOXs) are essential for the biosynthesis of specialized pro-resolving lipid mediators as a segment of an active process of acute inflammation in splenocardiac manner. In contrast, young 12/15LOX−/− mice use a compensatory mechanism that amplifies epoxyeicosatrienoic acid mediators after myocardial infarction, improving cardiac repair, function, and survival. Next, we tested whether deletion of 12/15LOX impacted the genesis of chronic inflammation in progressive aging. To test the risk factor of aging, we used the inter-organ hypothesis and assessed heart and spleen leukocyte population along with the number of inflammation markers in age-related 12/15LOX−/− aging mice (2 months, 6 months, 13 months) and compared with C57BL/6 J (WT; wild type) as controls (2 months). The 12/15LOX−/− aging mice showed an age-related increase in spleen mass (hypersplenism) and decreased marginal zone area. Results suggest increased interstitial fibrosis in the heart marked with the inflammatory mediator (PGD2) level in 12/15LOX−/− aging mice than WT controls. From a cellular perspective, the quantitative measurement of immune cells indicates that heart and spleen leukocytes (CD11b+ and F4/80+ population) were reduced in 12/15LOX−/− aging mice than WT controls. At the molecular level, analyses of cytokines in the heart and spleen suggest amplified IFN-γ, with reduced COX-1, COX-2, and ALOX5 expression in the absence of 12/15LOX-derived mediators in the spleen. Thus, aging of 12/15LOX−/− mice increased spleen mass and altered spleen and heart structure with activation of multiple molecular and cellular pathways contributing to age-related integrative and inter-organ inflammation.

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References

  1. Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity. 2013;39(5):806–18.

    Article  CAS  Google Scholar 

  2. Halade GV, Norris PC, Kain V, Serhan CN, Ingle KA. Splenic leukocytes define the resolution of inflammation in heart failure. Sci Signal. 2018;11(520):eaao1818. https://doi.org/10.1126/scisignal.aao1818.

  3. Swirski FK, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612–6.

    Article  CAS  Google Scholar 

  4. Gowda SB, et al. Sphingosine-1-phosphate interactions in the spleen and heart reflect extent of cardiac repair in mice and failing human hearts. Am J Physiol Heart Circ Physiol. 2021;321(3):H599–611.

    Article  CAS  Google Scholar 

  5. Adel S, et al. Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins. Proc Natl Acad Sci U S A. 2016;113(30):E4266–75.

    Article  CAS  Google Scholar 

  6. Halade GV, et al. Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction. Aging (Albany NY). 2016;8(11):2611–34.

    Article  CAS  Google Scholar 

  7. Kain V, Van Der Pol W, Mariappan N, Ahmad A, Eipers P, Gibson DL, et al. Obesogenic diet in aging mice disrupts gut microbe composition and alters neutrophil:lymphocyte ratio, leading to inflamed milieu in acute heart failure. FASEB J. 2019;33:6456–9.

  8. Rorholt M, et al. Risk of cardiovascular events and pulmonary hypertension following splenectomy — a Danish population-based cohort study from 1996–2012. Haematologica. 2017;102(8):1333–41.

    Article  Google Scholar 

  9. Robinette CD, Fraumeni JF Jr. Splenectomy and subsequent mortality in veterans of the 1939–45 war. Lancet. 1977;2(8029):127–9.

    Article  CAS  Google Scholar 

  10. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92–101.

    Article  CAS  Google Scholar 

  11. Lopez-Otin C, et al. The hallmarks of aging. Cell. 2013;153(6):1194–217.

    Article  CAS  Google Scholar 

  12. Münzel T, et al. Environmental noise and the cardiovascular system. J Am Coll Cardiol. 2018;71(6):688–97.

    Article  Google Scholar 

  13. Halade GV, Kain V, Tourki B, Jadapalli JK. Lipoxygenase drives lipidomic and metabolic reprogramming in ischemic heart failure. Metabolism; 2019;96:22–32.

  14. Kain V, et al. Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction. J Mol Cell Cardiol. 2018;118:70–80.

    Article  CAS  Google Scholar 

  15. Ingle KA, et al. Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol. 2015;309(11):H1827–36.

    Article  CAS  Google Scholar 

  16. Halade GV, Kain V, Ingle KA. Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology. Am J Physiol Heart Circ Physiol. 2018;314(2):H255-h267.

    Article  Google Scholar 

  17. Ma Y, et al. Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ Res. 2013;112(4):675–88.

    Article  CAS  Google Scholar 

  18. Kain V, et al. Activation of EP4 receptor limits transition of acute to chronic heart failure in lipoxygenase deficient mice. Theranostics. 2021;11(6):2742–54.

    Article  CAS  Google Scholar 

  19. Kayama Y, et al. Cardiac 12/15 lipoxygenase–induced inflammation is involved in heart failure. J Exp Med. 2009;206(7):1565–74.

    Article  CAS  Google Scholar 

  20. Dioszeghy V, et al. 12/15-lipoxygenase regulates the inflammatory response to bacterial products in vivo. J Immunol. 2008;181(9):6514.

    Article  CAS  Google Scholar 

  21. Middleton MK, et al. Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease. J Exp Med. 2006;203(11):2529–40.

    Article  CAS  Google Scholar 

  22. AdwanShekhidem H, et al. Telomeres and longevity: a cause or an effect? Int J Mol Sci. 2019;20(13):3233.

    Article  Google Scholar 

  23. Sager HB, Kessler T, Schunkert H. Monocytes and macrophages in cardiac injury and repair. J Thorac Dis. 2017;9(Suppl 1):S30-s35.

    Article  Google Scholar 

  24. Mosser DM, Hamidzadeh K, Goncalves R. Macrophages and the maintenance of homeostasis. Cell Mol Immunol. 2021;18(3):579–87.

    Article  CAS  Google Scholar 

  25. Honold L, Nahrendorf M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ Res. 2018;122(1):113–27.

    Article  CAS  Google Scholar 

  26. Marques RM, Gonzalez-Nunez M, Walker ME, Gomez EA, Colas RA, Montero-Melendez T, et al. Loss of 15-lipoxygenase disrupts Treg differentiation altering their pro-resolving functions. Cell Death Differ. 2021;28:3140–60.

  27. Berger A. Th1 and Th2 responses: what are they? BMJ. 2000;321(7258):424.

    Article  CAS  Google Scholar 

  28. Das J, et al. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med. 2009;206(11):2407–16.

    Article  CAS  Google Scholar 

  29. Murphy SP, et al. Inflammation in heart failure: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(11):1324–40.

    Article  Google Scholar 

  30. Kain V, Prabhu SD, Halade GV. Inflammation revisited: inflammation versus resolution of inflammation following myocardial infarction. Basic Res Cardiol. 2014;109(6):444.

    Article  Google Scholar 

  31. Emami H, et al. Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. JACC Cardiovasc Imaging. 2015;8(2):121–30.

    Article  Google Scholar 

  32. Tourki B, et al. Lipoxygenase inhibitor ML351 dysregulated an innate inflammatory response leading to impaired cardiac repair in acute heart failure. Biomed Pharmacother. 2021;139:111574.

    Article  CAS  Google Scholar 

  33. Halade GV, et al. Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury. J Leukoc Biol. 2018;104(6):1173–86.

    Article  CAS  Google Scholar 

  34. Halade GV, et al. Interaction of 12/15-lipoxygenase with fatty acids alters the leukocyte kinetics leading to improved postmyocardial infarction healing. Am J Physiol Heart Circ Physiol. 2017;313(1):H89-h102.

    Article  Google Scholar 

  35. Zaman R, Hamidzada H, Epelman S. Exploring cardiac macrophage heterogeneity in the healthy and diseased myocardium. Curr Opin Immunol. 2021;68:54–63.

    Article  CAS  Google Scholar 

  36. Turner VM, Mabbott NA. Influence of ageing on the microarchitecture of the spleen and lymph nodes. Biogerontology. 2017;18(5):723–38.

    Article  Google Scholar 

  37. Molawi K, et al. Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med. 2014;211(11):2151–8.

    Article  CAS  Google Scholar 

  38. Kaiko GE, et al. Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology. 2008;123(3):326–38.

    Article  CAS  Google Scholar 

  39. Lafaille JJ. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev. 1998;9(2):139–51.

    Article  CAS  Google Scholar 

  40. Mangan PR, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441(7090):231–4.

    Article  CAS  Google Scholar 

  41. Aw D, et al. Disorganization of the splenic microanatomy in ageing mice. Immunology. 2016;148(1):92–101.

    Article  CAS  Google Scholar 

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Funding

This work was supported in part by the National Institutes of Health (HL132989 and HL144788) to GVH.

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  1. Department of Medicine, Division of Cardiovascular Sciences, University of South Florida, Tampa, FL, 33602, USA

    Vasundhara Kain, Yusuf Mat & Ganesh V. Halade

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  1. Vasundhara Kain
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  2. Yusuf Mat
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  3. Ganesh V. Halade
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Correspondence to Ganesh V. Halade.

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11357_2021_496_MOESM1_ESM.pptx

Fig. 1: Detailed flow cytometry strategy for LV and spleen mononuclear cells. Fig. 2: Aging of 12/15LOX-/- mice progressively increased fibrosis and cardiomyocyte area in the heart. (A). Scatter plot representing quantification of collagen density in left ventricular (LV) of 12/15LOX-/- aging mice. (B). Graph representing cardiomyocyte area of LV stained by wheat gram agglutinin (WGA). 4–5 images/mouse, n = 5 mice/group. Data is representative of average±SEM; *p<0.05 vs. WT (2mo), # p<0.05 vs. 12/15LOX-/- (2 mo) by one-way analysis of variance (ANOVA). (PPTX 99 KB)

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Kain, V., Mat, Y. & Halade, G.V. Interaction of aging with lipoxygenase deficiency initiates hypersplenism, cardiac dysfunction, and profound leukocyte directed non-resolving inflammation. GeroScience 44, 1689–1702 (2022). https://doi.org/10.1007/s11357-021-00496-x

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  • DOI: https://doi.org/10.1007/s11357-021-00496-x

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