Projects Area A: Signal Proteins and cytokines
CCR8 is known to be expressed on Tregs and plays a crucial role in (chronic) immune responses. We identified CCR8 expression on CCL17+ DCs, which migrate towards its major ligand CCL1. Here, we will characterize CCR4-independent mechanisms of auto-/paracrine effects and mediators in cDCs and T cells (Aim 1), analyze and confirm the binding of CCL17 to CCR8 and explore receptors addressed by CCL17-chemokine heterodimers (Aim 2), and study the role of CCR8 in atherosclerosis (Aim 3). Thus, we aim at exploring how CCR8 contributes to recruitment and homeostasis of DC-subsets and their interaction with Tregs in the context of atherosclerosis
A02: Physical and functional interactions of chemokines with potent inflammatory effectors in atherosclerosis: focus on galectins
Our preliminary data indicate that inflammatory effector proteins such as chemokines and galectins interact with hitherto unknown consequences for atherosclerotic plaque formation. Therefore we will map interactions of chemokines with galectins in Aim 1 and will characterize affinities and interfaces of the binding partners in Aim 2 allowing the engineering of antagonists and variants in Aim 3 to investigate in Aim 4 functional effects of chemokine-galectin interactions by recruitment assays in vitro and in mouse models of atherosclerosis.
A03: The MIF protein/receptor network in atherosclerosis: mechanisms, novel members, and specific therapeutic strategies
opMIF is an atypical chemokine (CK) that promotes atherosclerosis through CXCR2/4-dependent leukocyte recruitment. Based on results of the first funding period, we will study the entire MIF protein network in atherosclerosis; i.e. dissect the interplay between MIF and MIF-2 in atherogenesis and B cell autoreactivity (Aim 1), study previously unrecognized MIF gene products (MIF-3/4, MIF-AS1-lncRNA) (Aim 2), elucidate interactions between MIF proteins and classical CKs (Aim 3), and develop the identified CXCR ectodomain peptides into next-generation MIF protein-specific mimics as proof-of-concept atherosclerosis blockers (Aim 4).
We have shown that gut hormone based polyagonist treatment targeting hypothalamic receptors improves obesity, dyslipidemia, and atherosclerosis. Building on our results in the first phase of this collaborative consortium grant, we propose to dissect such neuroendocrine circuitry functionally contributing to atherogenesis (Aim 1) and to examine the functional relevance of novel downstream components of these periphery-brain axes for the treatment of cardio-vascular disease (Aim 2). Based on these studies we ultimately aim to develop novel therapeutic strategies to effectively treat atherosclerosis in conjunction with reversing obesity and rescuing impaired glucose metabolism.
We identified two novel master switches of T cell reactivity in atherosclerosis: the immune check-point regulator cbl-b and the amino acid homoarginine (hArg). cbl-b-deficiency increases athero-sclerosis and T cell activation by modulating co-stimulation. hArg, previously established as being protective in CVD, suppresses T cell reactivity. We will investigate how T cell regulation by cbl-b or hArg modifies T cell immunoreactivity and atherosclerosis (Aim 1) and explore their potential as therapeutic targets for CVD (Aim 2). Further we will study how co-stimulatory molecules and meta-bolites in T-cells and antigen presenting cells are altered in murine and human atherogenesis (Aim 3) and verify their suitability as biomarkers in several CVD patient cohorts (Aim 4).
Recent data indicate that the activity of inflammatory processes is controlled in a circadian fashion. We hypothesize that distinct proinflammatory events within atherosclerotic lesions exhibit progressive cycles of accelerated circadian activity. Thus, we aim at generating a map of circadian gene and protein expression in advanced atherosclerotic lesions (Aim 1), dissecting the circadian control of core processes of plaque destabilization (Aim 2), defining the relevance of superior master regulators such as local innervation and adrenal hormones (Aim 3), and generating evidence for the relevance of time-optimized intervention in mouse models of atherosclerosis (Aim 4).
topA07: Comparative fate mapping and interactions of macrophages and smooth muscle cells in atherosclerosis
Macrophages and vascular smooth muscle cells (SMCs) are the predominant resident cell populations in the arterial vessel wall and can therefore be considered as first responders to inflammatory stimuli in atherosclerosis. However, the complex interplay of tissue resident cells within the arterial vessel wall is still incompletely understood. Therefore, the central aim of this project is to dissect the fate (Aim 1) and mutual interactions (Aim 2) of the different SMC and macrophage populations as well as to determine their contribution to atherosclerotic plaque formation (Aim 3).
A10: Role of the atypical chemokine receptor ACKR1/DARC in the myeloid pathogenesis of atherosclerosis
Individuals of African ancestry carry a variant of the gene encoding atypical chemokine receptor 1 (ACKR1), which abolishes its expression in erythroid cells. The absence of ACKR1 leads to changes in hematopoiesis with phenotypically distinct myeloid cells. We aim to detail how the lack of ACKR1 impacts atherosclerosis development. In particular, we will characterize a role of “alternatively armed” neutrophils (Aim 1) and classical monocytes (Aim 2) occurring without erythroid ACKR1 in atherogenesis. In addition, we will examine the origin and function of non-classical monocytes in this context (Aim 3) and finally translate these findings into humans (Aim 4).