3D culture of Erdheim-Chester disease tissues unveils histiocyte metabolism as a new therapeutic target

Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

“…Enhanced glycolisis is a hallmark of activated macrophages (53)(54)(55)(56)(57). Recents studies of SSc patients undergoing positron emission tomography using the glucose analogue tracer 18 fluorodeoxyglucose revealed both increased glucose uptake (58).…”

“…Levels of succinate are up-regulated in lung myofibroblasts of patients with idiopathic pulmonary fibrosis, where they induce TGF-b1, hypoxia-inducible factor-1alpha (HIF-1a), and fibroblast differentiation (58). Of note, succinate levels stabilize HIF-1a and promote IL-1b expression (53); this process is inhibited by itaconate, an anti-inflammatory metabolite required for the activation of the anti-inflammatory transcription factor Nrf2 by lipopolysaccharide in mouse and human macrophages, thus enabling Nrf2 to increase the expression of downstream antioxidant genes as NAD(P)H Quinone Dehydrogenase 1 (60,61). Interestingly though, the Nrf2 pathway is highly down-regulated in human and SSc mice with detrimental consequences on inflammation and fibrosis.…”

“…However, current evidence is conflicting and synthesis and degradation of fatty acids were linked to inflammasome activation in different studies, perhaps indicating that imbalance itself may activate an inflammatory response. It is also possible that these metabolic pathways activate a common intermediate mediator able to directly activate the NLRP3 inflammasome, the main candidate being mitochondrial reactive oxygen species (mtROS) (53). The w-3 PUFA, docosahexaenoic acid (DHA), inhibits the activation of caspase-1, thus lowering the production of active IL-1b (64,65).…”

Erdheim-Chester disease: An in vivo human model of Mϕ activation at the crossroad between chronic inflammation and cancer

“…Culture of ECD tissues, obtained for diagnostic purposes, in bioreactor revealed that CD68 + histiocytes retained constitutive ERK phosphorylation (Fig. 2B) and the capability to secrete prototypical cytokines and chemokines; both features were reverted upon BRAF inhibition with vemurafenib 82 . Moreover, mutated ECD histiocytes reprogrammed metabolism toward aerobic glycolysis (Warburg effect), as indicated by up‐regulated expression of the Glucose transporter‐1 (Glut‐1) and lactate production 82 ; again, vemurafenib treatment counteracted both events, 82 thus indicating that rewired metabolism is a mutation‐driven hallmark of histiocytes and a feasible therapeutic target.…”

“…2B) and the capability to secrete prototypical cytokines and chemokines; both features were reverted upon BRAF inhibition with vemurafenib 82 . Moreover, mutated ECD histiocytes reprogrammed metabolism toward aerobic glycolysis (Warburg effect), as indicated by up‐regulated expression of the Glucose transporter‐1 (Glut‐1) and lactate production 82 ; again, vemurafenib treatment counteracted both events, 82 thus indicating that rewired metabolism is a mutation‐driven hallmark of histiocytes and a feasible therapeutic target. Maladaptive metabolic changes are instrumental to survival of cancer cells, whose energy demands for deranged proliferation and protein synthesis exceed physiologic capacity 83‐85 .…”