Research

Prior history of our research programs:

1) Inflammation, influenza lung infection and aging. We examined if a vaccine consisting of a TLR5 agonist linked to an IAV antigen, protected aged mice during IAV infection. Although this vaccine provides some protection, it is still less efficacious than its use in young mice¹. This prompted us to investigate how aging impacts IAV infection. We were the first to comprehensively examine how aging impacts alveolar macrophages (AMs)², cells that provide host defense and inflammation resolution³. We found that aging downregulates cell cycle pathways in AMs, reduces AM population size, and impairs AMs to efferocytose neutrophils². We demonstrated that aging leads to an accumulation of neutrophils early after IAV infection to induce mortality⁴. By depleting neutrophils, we reduced lung inflammation and rescued aged mice from lethality caused by IAV infection ⁴. This demonstrates that reducing inflammation during IAV infection improves survival with aging. Finally, we demonstrated that macrophage migratory inhibitory factor promotes immune pathology during IAV via upregulating a mitophagy protein, Parkin, to impair type I IFNs⁵.

2) Vascular inflammation, atherosclerosis and aging. Although aging is a strong risk factor for atherosclerosis, the biological effects of aging on atherogenesis, independent of chronic hyperlipidemia, have never been established. We examined this question in mice. Without hyperlipidemia, we were the first to report that aortic smooth muscle cells (SMCs) exhibit increased productions of IL-6 and CCL-2 with aging, which are dependent on the TLR signal adaptor MyD88⁶. We next showed that during chronic hyperlipidemia, aging enhances macrophage recruitment into the vasculature⁷. Recently, we demonstrated that aortic mitochondrial dysfunction, and elevated IL-6 levels co-exist in a positive feedback loop prior to hyperlipidemia and this directly enhances atherosclerosis with aging ⁸. Collectively, our studies have identified novel pathways by which aging enhances atherosclerosis.

3) Organ transplant rejection and aging. We were the first to demonstrate that aged memory CD4⁺ T cells produce IL-17 to enhance skin allograft rejection in mice⁹. We also found that naive, rather than memory, CD8⁺ T cells exhibit rapid alloimmune responses in vitro¹⁰, which contrasts with the current dogma that memory T cells elicit rapid production of cytokines upon reactivation ¹¹. Finally, we discovered a novel role of age-associated B cells in impairing immune regulation to allografts with aging¹²

4) Innate immunity, systemic viral infection and aging. We were the first to examine the impact of aging on TLR signaling in vitro and in vivo in mice¹³. While TLR function is preserved in myeloid dendritic cells (DCs) with aging¹³, we found that aging impairs the ability of plasmacytoid DCs to produce type I interferons (IFN), which reduces the clearance of systemic herpes viruses¹⁴. We demonstrated that Natural Killer (NK) T cells exhibit exuberant IL-17 levels during systemic herpes infection with aging, which induces lethal liver pathology¹⁵. Depleting IL-17 rescues aged mice from lethality during infection¹⁵. Previously, the dogma was that aging leads to reduced immunity to induce death during infection^{16, 17}. Our study was the first to show that aging induces exaggerated innate immunity that causes death during viral infection¹⁵.

References

1. Leng J, Stout-Delgado HW, Kavita U, Jacobs A, Tang J, Du W, Tussey L and Goldstein DR. Efficacy of a vaccine that links viral epitopes to flagellin in protecting aged mice from influenza viral infection. Vaccine. 2011;29:8147-8155.

2. Wong CK, Smith CA, Sakamoto K, Kaminski N, Koff JL and Goldstein DR. Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. The Journal of Immunology. 2017;199:1060-1068.

3. Hussell T and Bell TJ. Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol. 2014;14:81-93.

4. Kulkarni U, Zemans RL, Smith CA, Wood SC, Deng JC and Goldstein DR. Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality. Mucosal Immunology. 2019;2:545-554.

5. Smith CA, Tyrell DJ, Kulkarni UA, Wood S, Leng L, Zemans RL, Bucala R and Goldstein DR. Macrophage migration inhibitory factor enhances influenza-associated mortality in mice. JCI Insight. 2019;4.

6. Song Y, Shen H, Schenten D, Shan P, Lee PJ and Goldstein DR. Aging Enhances the Basal Production of IL-6 and CCL2 in Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol. 2012;1:103-9.

7. Du W, Wong C, Song Y, Shen H, Mori D, Rotllan N, Price N, Dobrian AD, Meng H, Kleinstein SH, Fernandez-Hernando C and Goldstein DR. Age-associated vascular inflammation promotes monocytosis during atherogenesis. Aging Cell. 2016;15:766-777.

8. Tyrrell DJ, Blin M, Song J, Wood S, Zhang M, Beard DA and Goldstein DR. Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis. Circulation Research. 2020;126:298–314.

9. Tesar BM, Du W, Shirali AC, Walker WE, Shen H and DR. G. Aging Augments IL-17 T-Cell Alloimmune Responses. Am J Transplant. 2009;9:54-63.

10. Du W, Shen H, Galan A and Goldstein DR. An Age-Specific CD8+ T Cell Pathway That Impairs the Effectiveness of Strategies To Prolong Allograft Survival. The Journal of Immunology. 2011;187:3631-40.

11. Brook MO, Wood KJ and Jones ND. The Impact of Memory T Cells on Rejection and the Induction of Tolerance. Transplantation. 2006;82:1-9.

12. Mori DN, Shen H, Galan A and Goldstein DR. Aged B cells alter immune regulation of allografts in mice. European Journal of Immunology. 2016;46:2650-2658.

13. Tesar BM, Walker WE, Unternaehrer J, Joshi NS, Chandele A, Haynes L, Kaech S and Goldstein DR. Murine myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging. Aging Cell. 2006;5:473-486.

14. Stout-Delgado HW, Yang X, Walker WE, Tesar BM and Goldstein DR. Aging Impairs IFN Regulatory Factor 7 Up-Regulation in Plasmacytoid Dendritic Cells during TLR9 Activation. J Immunol. 2008;181:6747-6756.

15. Stout-Delgado HW, Du W, Shirali AC, Booth CJ and Goldstein DR. Aging Promotes Neutrophil-Induced Mortality by Augmenting IL-17 Production during Viral Infection. Cell Host Microbe. 2009;6:446-456.

16. Haynes L and SL S. Why Aging T cells Fail: Implications for vaccination. Immunity. 2006;24:663-666.

17. Miller RA. The aging immune system: primer and prospectus. Science. 1996;273:70-4.

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