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Protection of cardiometabolic inflammation by modulation of myeloid glutamine homeostasis

Periodic Reporting for period 2 - PROGLUTASIS (Protection of cardiometabolic inflammation by modulation of myeloid glutamine homeostasis)

Reporting period: 2018-10-01 to 2020-03-31

Cardiovascular diseases (CVD) are the leading cause of death worldwide with 17 million deaths every year and represent a major public health challenge. Limited pharmaceutical innovation, declining translational success and clinical failures mandate a detailed exploration of novel and integrated therapeutic approaches for treating the metabolic syndrome and to meet the global therapeutic demand. glutamine is the most abundant amino acid in the plasma and an important energy source through glutaminolysis and (ii) a strong inverse association has been systematically observed between glutamine-to-glutamate ratio and cardiometabolic traits including obesity, insulin-resistance, cardiovascular diseases, or the MetS as a whole. Although some studies suggest that these beneficial metabolic effects could be attributed to a role of glutamine on the immune cell response, the underlying mechanisms are poorly understood. Our overall goal was to decipher 1) the regulation of glutamine homeostasis in cardiometabolic disease and the impact of glutaminolysis on 2) hematopoiesis and 3) macrophage effector functions. These findings may have broad therapeutic implications in pathologic settings driven by chronic metabolic perturbations as glutamine metabolism could potentially synergize with anti-inflammatory therapies that are currently being tested in clinical trials.
- At this stage of the project, we have completed WP1.1 WP2.4 and the full WP3 and results have been combined in a manuscript that we have just recently submitted entitled ‘Non-canonical transamination metabolism of glutamine sustains efferocytosis by coupling oxidative phosphorylation to oxidative stress buffering’ by Merlin et al.,
The abstract is provided below and the full version of the manuscript is attached to the Annex.
Abstract: Tissue macrophages rely on tightly integrated metabolic rewiring to maintain tissue integrity and continuously clear neighboring cells that turnover during homeostasis and disease. Glutaminase (Gls1) converts glutamine to glutamate to fuel anabolic reactions and support cellular redox balance. Here, we identify a critical role for Gls1 in promoting apoptotic cell (AC) clearance by macrophages (efferocytosis) after interleukin-4 (IL-4) stimulation or upon multiple rounds of AC exposure, which are two physiologic paradigms. Mice selectively lacking macrophage glutaminolysis showed defective efferocytosis in vivo and significant pathologic consequences in atherosclerotic lesions of fat-fed ApoE-/- mice. A strong correlation between Gls1 expression and plaque necrosis was also discovered in human atherosclerotic plaque. Most cells utilize glutamate dehydrogenase (Glud1) to fuel a-ketoglutarate (aKG) into the tricarboxylic acid (TCA) cycle for anapleurosis and epigenetic modifications. However, high- throughput transcriptional and metabolic profiling unexpectedly revealed that macrophage effector and clearance functions rely on a non-canonical transaminase pathway. Specifically, glutamate is channeled into the malate-aspartate shuttle by aspartate aminotransferase (GOT)-dependent transamination in order to meet the demand for high energy cytoskeletal rearrangements and cellular detoxification requirements. Macrophages are highly dependent on these series of reactions, as pharmacologic modulation of enzymes within these pathways impaired efferocytosis. Thus, our non-biased systems approach identifies that efficient clearance of ACs has a previously unknown reliance on non-canonical glutamine metabolism.
This work has been presented at Novartis in Cambridge, USA; EAS course in Vienna; Icola meeting in Seoul, Korea and the national society of atherosclerosis, NSFA, Biarritz, France.
- Regarding WP1.2 to 1.4 Florent Murcy, who is an internal medicine physician, started his PhD in September 2019. He already completed WP1.4 looking at the association between glutamine-to-glutamate and CVD events in 1500 patients from the MESA study. We found a strong association between this ratio and CVD events in this cohort and we are pursuing WP1.2 and 1.3 to identify the molecular mechanism responsible for this association in preclinical models
-Regarding WP2.1 to 2.3 our preliminary data argue against a major role of Gls1 in hematopoietic stem and progenitor cell proliferation and fate in control background. Thus, we have backcrossed these mice on a ApoE-/- mouse model known to exacerbate the expansion of myeloid cells. This is an ongoing work.
- We have also extended our work beyond expectations as we have unexpectedly identified a completely new role of macrophage glutaminolysis in spinal cord macrophages controlling sympathetic tone of thermogenic adipose tissue. The abstract is provided below. We are currently working on the manuscript.
Abstract; Macrophages play a key role in host defense against pathogens and contribute to tissue homeostasis. Macrophages isolated from different tissues possess specific gene signature and their functions are adapted to their local microenvironment. Adipose tissue macrophages control the expandability of the visceral adipose tissue through their switch from an anti-inflammatory to a pro-inflammatory phenotype and the thermogenic process of other adipose depots by modulation of the sympathetic tone. Here, we report that mice with defective macrophage glutaminolysis (macrophage specific Gls1 deficiency) display impaired visceral adipose tissue macrophage alternative activation that contributes to augmented visceral fat storage. These mice also exhibited dysfunctional subcutaneous and brown adipose tissue thermogenic response. Mechanistically, we found that macrophage glutaminolysis deficiency limited activation of spinal cord glutamatergic neurons required for activation of sympathetic tone-dependent thermogenesis by limiting their interaction with glutamatergic neuron-associated macrophages (GAMs). Collectively, our study reveals a previously unappreciated homeostatic role for macrophage glutaminolysis in the control of visceral adipose tissue inflammation and spinal cord-dependent sympathetic tone of thermogenic adipose depots. Disruption of these circuits resulted in metabolic imbalance and obesity.