To date, no immunomodulatory therapies for chronic heart failure (HF) have been successfully translated to clinical practice. Recently, we described a heretofore unappreciated adverse cardiosplenic axis in ischemic HF, with pro-inflammatory splenocytes homing to the failing heart to induce tissue injury. This exciting discovery supports a new approach to immunomodulation - one that directly targets specific leukocyte and/or splenocyte populations. Our recent studies suggest an important role for splenic marginal zone (MZ) macrophages in the genesis of inflammation and LV remodeling in ischemic HF. Comprised of two cell types - CD-169+ marginal metallophilic macrophages (MMMs) and SIGN-R1+MARCO+ MZ macrophages (MZMs) - these specialized macrophages are pro-inflammatory and broad immune activators. Based on our preliminary data, we hypothesize that MZ macrophage activation is essential for chronic inflammation, LV remodeling, and disease progression in HF, and thereby are key cellular targets for immunomodulation. We outline three Aims to test this hypothesis.
In Aim 1, we will delineate trafficking of MMMs/MZMs in chronic HF using a murine coronary ligation model and sham-operated controls. MZ macrophages and their activation profiles will be measured in heart, blood, spleen, and mediastinal lymph nodes by flow cytometry and immunohistochemistry at several time points after ligation, both in the absence and presence of splenectomy, and correlated with LV remodeling and inflammation. The infiltration dynamics of MZ macrophages will be determined by heterotopic transplantation of CD45.2 failing hearts into CD45.1 HF mice with or without splenectomy, and measuring the temporal kinetics of donor- and recipient-derived MZM and MMM loss vs. accumulation in the transplanted heart.
In Aim 2, we will define the role of MZ macrophages in the pathogenesis of inflammation and LV remodeling by selectively (and reversibly) depleting MMMs and MZMs during HF using both liposomal (clodronate) and genetic (CD169-DTR Tg mice) approaches, and then evaluating the effects of loss-of-function on inflammation, immune cell profiles, and LV and splenic remodeling.
In Aim 3, we will establish whether MZ macrophages are essential drivers of the detrimental cardiosplenic axis in ischemic HF. CD45.2 mononuclear splenocytes from CD169-DTR Tg mice with HF will be adoptively transferred into CD45.1 naive mice, with or without prior MZ macrophage ablation. We will also transfer CD45.1 HF splenocytes into CD45.2 CD169-DTR Tg mice and then chronically deplete MZ macrophages in recipients. The effects of splenocyte transfer on LV/splenic remodeling, inflammation, and immune cell profiles will be measured in recipient mice. In parallel, we will evaluate the ability of MZ macrophages from HF and sham mice to activate naive splenic T- lymphocytes in vitro. These important studies will further our understanding of the cellular basis for inflammatory and immune activation in chronic ischemic HF, and provide innovative perspectives as to the fundamental underpinnings of the recently discovered pro-inflammatory and tissue-injurious cardiosplenic axis.

Public Health Relevance

Heart failure (HF), a progressive disease with a poor prognosis, is characterized by inflammation, and yet no therapies that modulate inflammation have been successfully employed in patients. We suggest a new perspective on inflammation in HF - that it is in large part driven by pathological changes in the spleen and splenic immune cells (i.e., an adverse cardiosplenic axis). We propose that: 1) a specialized population of immune cells - splenic marginal zone macrophages - are key mediators of this cardiosplenic axis and are central to the development of inflammation and inflammation-related heart damage in HF, and 2) therapeutically targeting these cells represents a better approach to alleviating inflammation in HF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125735-04
Application #
9412869
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2015-03-10
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Patel, Bindiya; Ismahil, Mohamed Ameen; Hamid, Tariq et al. (2017) Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure. PLoS One 12:e0170781
Lynch 4th, Thomas L; Ismahil, Mohamed Ameen; Jegga, Anil G et al. (2017) Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. J Mol Cell Cardiol 102:83-93
Kain, Vasundhara; Liu, Fei; Kozlovskaya, Veronika et al. (2017) Resolution Agonist 15-epi-Lipoxin A4 Programs Early Activation of Resolving Phase in Post-Myocardial Infarction Healing. Sci Rep 7:9999
Bansal, Shyam S; Ismahil, Mohamed Ameen; Goel, Mehak et al. (2017) Activated T Lymphocytes are Essential Drivers of Pathological Remodeling in Ischemic Heart Failure. Circ Heart Fail 10:e003688
Yanamandala, Mounica; Zhu, Wuqiang; Garry, Daniel J et al. (2017) Overcoming the Roadblocks to Cardiac Cell Therapy Using Tissue Engineering. J Am Coll Cardiol 70:766-775
Evonuk, Kirsten S; Prabhu, Sumanth D; Young, Martin E et al. (2017) Myocardial ischemia/reperfusion impairs neurogenesis and hippocampal-dependent learning and memory. Brain Behav Immun 61:266-273
Hamid, Tariq; Prabhu, Sumanth D (2017) Immunomodulation Is the Key to Cardiac Repair. Circ Res 120:1530-1532
Halade, Ganesh V; Kain, Vasundhara; Ingle, Kevin A et al. (2017) Interaction of 12/15-lipoxygenase with fatty acids alters the leukocyte kinetics leading to improved postmyocardial infarction healing. Am J Physiol Heart Circ Physiol 313:H89-H102
Kingery, Justin R; Hamid, Tariq; Lewis, Robert K et al. (2017) Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol 112:19
Halade, Ganesh V; Kain, Vasundhara; Black, Laurence M et al. (2016) Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction. Aging (Albany NY) 8:2611-2634

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