Myeloid-specific deletion of NOX2 prevents the metabolic and neurologic consequences of high fat diet

Abstract

High fat diet-induced obesity is associated with inflammatory and oxidative signaling in macrophages that likely participates in metabolic and physiologic impairment. One key factor that could drive pathologic changes in macrophages is the pro-inflammatory, pro-oxidant enzyme NADPH oxidase. However, NADPH oxidase is a pleiotropic enzyme with both pathologic and physiologic functions, ruling out indiscriminant NADPH oxidase inhibition as a viable therapy. To determine if targeted inhibition of monocyte/macrophage NADPH oxidase could mitigate obesity pathology, we generated mice that lack the NADPH oxidase catalytic subunit NOX2 in myeloid lineage cells. C57Bl/6 control (NOX2-FL) and myeloid-deficient NOX2 (mNOX2-KO) mice were given high fat diet for 16 weeks, and subject to comprehensive metabolic, behavioral, and biochemical analyses. Data show that mNOX2-KO mice had lower body weight, delayed adiposity, attenuated visceral inflammation, and decreased macrophage infiltration and cell injury in visceral adipose relative to control NOX2-FL mice. Moreover, the effects of high fat diet on glucose regulation and circulating lipids were attenuated in mNOX2-KO mice. Finally, memory was impaired and markers of brain injury increased in NOX2-FL, but not mNOX2-KO mice. Collectively, these data indicate that NOX2 signaling in macrophages participates in the pathogenesis of obesity, and reinforce a key role for macrophage inflammation in diet-induced metabolic and neurologic decline. Development of macrophage/immune-specific NOX-based therapies could thus potentially be used to preserve metabolic and neurologic function in the context of obesity.

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

“…Infact, Diet‐induced hepatic neutrophil, macrophage, and T‐cell infiltration are trademarks of NAFLD progression and pathogenesis . The reduction in hepatic macrophages in livers of NOX2 −/− mice is consistent with a recent report of attenuated macrophage infiltration into WAT in myeloid‐specific NOX2 −/− mice . Altered number of liver‐infiltrating immune cells in NOX2 −/− mice also suggest reduced activation of inflammatory axes in these mice.…”

“…Hepatic accumulation of neutrophils, macrophages, and CD4 + T cells (e.g., T helper [Th]1 and Th17 subsets) correlates with NAFLD progression . NOX2 regulates hepatic immune cell infiltration and immune cell cytokine production . Notably, proinflammatory cytokines (e.g., IFN‐γ, TNF‐α, IL‐17A) are well‐established modulators of NAFLD pathogenesis .…”

“…(1,35,48) The reduction in hepatic macrophages in livers of NOX2 2/2 mice is consistent with a recent report of attenuated macrophage infiltration into WAT in myeloid-specific NOX2 2/2 mice. (36) Altered number of liver-infiltrating immune cells in NOX2 2/2 mice also suggest reduced activation of inflammatory axes in these mice. Proinflammatory cytokine production, by liver-infiltrating immune cells, is central to NAFLD pathogenesis.…”

“…(34,35) NOX2 regulates hepatic immune cell infiltration and immune cell cytokine production. (36) Notably, proinflammatory cytokines (e.g., IFN-c, TNF-a, IL-17A) are well-established modulators of NAFLD pathogenesis. (1,2,4,20) We therefore examined the role of NOX2 in the modulation of immune cell inflammatory vigor.…”

CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma

“…We recently identified that NOX2-derived superoxide from acute myeloid leukemia is crucial for mitochondrial transfer to occur in this malignancy (15). However, inhibitors of NOX2 are not clinically available, and moreover, toxicity may present a problem with such a strategy as deletion of NOX2 in humans frequently leads to death in the first decade of life (46). Here, our results identify CD38 as a viable molecular target to reduce mitochondrial transfer between nonmalignant and malignant cells, with drugs presently available for use and/or in advanced stages of preclinical development.…”