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Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of LXRa Signaling in Macrophages

Li, Yutian
http://orcid.org/0000-0002-5118-0916
http://rave.ohiolink.edu/etdc/view?acc_num=ucin159326971657815

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Acute and chronic inflammation are reflected by systemically greater abundance of proinflammatory cytokines and increased infiltration and activation of immune cells in various tissues. In particular, cardiac dysfunction is a common ailment associated with both acute and chronic inflammatory states. As a fundamental component of innate immunity, macrophages play critical roles in both initiating and resolving inflammation in the heart. In fact, macrophages are prominent cells that drive septic cardiomyopathy in animal models; and human monocytes/macrophages secrete more inflammatory cytokines in type 2 diabetic patients and positively correlate with atherosclerosis severity. Secreted and transmembrane protein 1 (Sectm1, also referred to as K12) is a type 1 transmembrane protein. The knowledge of Sectm1 function in human diseases is currently limited to its role as an alternative CD7 ligand to stimulate T cell proliferation. Whether Sectm1 plays a role in normal macrophage biology and inflammatory diseases has never been investigated. In this dissertation, we observed that mRNA levels of Sectm1a (mouse homolog of human Sectm1) was significantly increased in early time points (peak at 6 h), but reduced at later time points in LPS-treated bone marrow-derived macrophages (BMDMs) and spleen of wild-type (WT) mice injected with LPS. To determine the role of Sectm1a in macrophage activation and inflammation-induced cardiac injury, we generated a Sectm1a-knockout (KO) mouse model in which LPS-induced cardiac injury and mortality were greatly augmented. Further analysis revealed that inflammatory macrophages in hearts of KO-LPS mice was greatly accumulated, compared to WT-LPS controls. In accordance to the activated macrophage phenotype, lack of Sectm1a dramatically increased the production of inflammatory cytokines (TNFa, IL-6, and IL-1ß) and MCP-1 levels both in vitro (BMDMs) and in vivo (in serum and myocardium) after LPS challenge. Moreover, we detected significantly lower levels of proinflammatory cytokines when overexpressing Sectm1a in BMDMs, but not in cardiomyocytes. Most importantly, transplantation of Sectm1a-KO bone marrow cells into WT mice resulted in increased accumulation of inflammatory macrophages in the heart and aggravated cardiac dysfunction upon LPS challenge. These data suggest that ablation of Sectm1a induces cardiac dysfunction through activation of immune responses mediated by macrophages. Furthermore, RNA-sequencing results, along with bioinformatics analyses showed that many of the LXR? target genes are significantly downregulated in Sectm1a KO BMDMs. Furthermore, ablation of sectm1a hinders the nuclear translocation of LXRa in response to GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines. In addition, administration of GW3965 fails to rescue cardiac function in KO mice upon LPS injection. Notably, coimmuno- precipitation (Co-IP) results suggest potential physical interaction between Sectm1a and LXRa. Lastly, using chronic inflammation model induced by high-fat diet (HFD, 18-24 week) feeding, we also observed that infiltration of inflammatory monocytes/ macrophages in KO-hearts was dramatically increased, leading to aggravated cardiac dysfunction, compared to WT-HFD controls. In summary, this study defines a novel function of Sectm1a in macrophage biology, and identifies a new cellular mechanism for Sectm1a in the regulation of macrophage activation via LXRa signaling cascade, and its relationship to inflammation-induced cardiac injury.
Guochang Fan, Ph.D. (Committee Chair)
David Hui, Ph.D. (Committee Member)
Terence Kirley, Ph.D. (Committee Member)
Diego Perez-Tilve, Ph.D. (Committee Member)
Jack Rubinstein, M.D. (Committee Member)
David Wieczorek, Ph.D. (Committee Member)
129 p.
Immunology
macrophage; inflammation; cardiac function; cardiac inflammation; LXR

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Citations

  • Li, Y. (2020). Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of LXRa Signaling in Macrophages [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin159326971657815

    APA Style (7th edition)

  • Li, Yutian. Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of LXRa Signaling in Macrophages. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin159326971657815.

    MLA Style (8th edition)

  • Li, Yutian. "Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction Through Disruption of LXRa Signaling in Macrophages." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin159326971657815

    Chicago Manual of Style (17th edition)

ucin159326971657815
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This open access ETD is published by University of Cincinnati and OhioLINK.