Abstract
The intersection of bioactive lipids and inflammation is a central feature of immune cells during tissue injury,
particularly in macrophages. When homeostatic mechanisms fail to resolve inflammatory responses and/or
become maladaptive, chronic low-grade inflammatory conditions or excessive wound healing events can be
established. For example, lung fibrosis and atherosclerosis, in part, results from overactive tissue repair and
defective inflammation resolution, respectively. There are major knowledge gaps regarding the nature of the
lipid interactome in health and disease, and how it modulates inflammation to either exacerbate tissue damage
or promote resolution/repair. Thus, ‘defects in inflammation resolution programs’ is a major theme that runs
through this proposal. The specific goal of this grant is to mechanistically understand the immunoregulatory
crosstalk we have observed between a metabolic serine hydrolase – termed human carboxylesterase 1
(CES1) – and the lipid-sensing nuclear receptors PPARgamma and LXRalpha, which can affect macrophage phenotype
and function after exposure to ‘danger-associated molecules’, such as cytokines and oxidized low-density
lipoproteins (oxLDL). To attack this problem, we hypothesize that one function of CES1 in macrophages is to
regulate the levels of endogenous ligands that are sensed by PPARgamma and LXRalpha in the setting of resolving
inflammation, thus modulating the activity of these putative anti-inflammatory receptors. This will be tested with
two aims that will: (i) Characterize the cross talk between CES1 and the lipid-sensing receptors PPARgamma and
LXRalpha; (ii) Evaluate the mechanisms by which murine Ces1d (the mouse ortholog of human CES1) in lung
regulates the activity of ‘alternatively polarized’ macrophages in a pulmonary fibrosis model. Human monocyte-
derived macrophages with key genes knocked out and an innovative mouse model will be used to study the
effects of macrophage-activating stimuli on biochemical, genomic, and lipidomic outputs. The impact of this
project is that it will demonstrate how CES1 transduces extracellular signals that shape the immunophenotype
of macrophages. At this stage, the links between CES1 and the nuclear receptors PPARgamma and LXRalpha are
unclear; however, obtaining this knowledge would allow new and innovative ways to therapeutically temper the
activities of M1 and M2 macrophages that exacerbate atherosclerosis and lung fibrosis, respectively. Following
the successful completion of this project, we will better understand the mechanisms by which CES1 regulates
cellular levels of oxidized chemicals (oxylipins and oxysterols) that are formed in the context of lipid- and
chemical-driven inflammation. Further, we will have a better view of the subsequent interactions of these
compounds with proteins (e.g., ligand-activated transcription factors) in macrophages that ultimately shape
their cellular response to immune-polarizing stimuli in health and injury.