miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

Abstract

Key Points• miR-125b reduces mitochondrial respiration and promotes elongation of mitochondrial network through BIK and MTP18 silencing, respectively. • The miR-125b/BIK/MTP18 axis promotes adaptation of monocytes to inflammation.Metabolic changes drive monocyte differentiation and fate. Although abnormal mitochondria metabolism and innate immune responses participate in the pathogenesis of many inflammatory disorders, molecular events regulating mitochondrial activity to control life and death in monocytes remain poorly understood. We show here that, in human monocytes, microRNA-125b (miR-125b) attenuates the mitochondrial respiration through the silencing of the BH3-only proapoptotic protein BIK and promotes the elongation of the mitochondrial network through the targeting of the mitochondrial fission process 1 protein MTP18, leading to apoptosis. Proinflammatory activation of monocyte-derived macrophages is associated with a concomitant increase in miR-125b expression and decrease in BIK and MTP18 expression, which lead to reduced oxidative phosphorylation and enhanced mitochondrial fusion. In a chronic inflammatory systemic disorder, CD14 1 blood monocytes display reduced miR-125b expression as compared with healthy controls, inversely correlated with BIK and MTP18 messenger RNA expression. Our findings not only identify BIK and MTP18 as novel targets for miR-125b that control mitochondrial metabolism and dynamics, respectively, but also reveal a novel function for miR-125b in regulating metabolic adaptation of monocytes to inflammation. Together, these data unravel new molecular mechanisms for a proapoptotic role of miR-125b in monocytes and identify potential targets for interfering with excessive inflammatory activation of monocytes in inflammatory disorders. (Blood. 2016;128(26): 3125-3136)

The expression of miR‐125b in Nrf2‐silenced A549 cells exposed to hyperoxia and its relationship with apoptosis

“…Up‐regulation of miR‐125b expression maintained the body weight and survival of ALI mice and significantly reduced LPS‐induced pulmonary inflammation . Another study showed that increased miR‐125b through toll‐like receptor 4(TLR4) affected mitochondrial respiration and dynamics through BIK and MTP18 silencing, respectively, promoting pro‐inflammatory activation and apoptosis of monocytes . Nrf2 has attracted increased attention as a protective transcription factor.…”

MiR-125b Inhibits LPS-Induced Inflammatory Injury via Targeting MIP-1α in Chondrogenic Cell ATDC5

“…The mechanisms by which miRNAs are regulated and expressed under normal or disease conditions are currently of great interest. Although miR-125b has been implicated in various cancers [12, 25-27], and might contribute to persistent inflammation [28, 29], this is the first indication about the role of miR-125b in chondrocytes inflammatory response.…”

Cell‐intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg

“…At this time we know, for example, that human monocyte derived inflammatory macrophage produce TNF, IL-1β and IL-6, and exhibit broadly similar metabolic characteristics including increased glycolytic activity, diminished OXPHOS, the production of itaconate, increased oxidative stress, and the depletion of intracellular NADPH and NAD+ after LPS stimulation. 30,41,114 However, human monocyte-derived macrophages do not express NOS2 or make NO after LPS stimulation, [115][116][117][118][119] and therefore will not experience the pseudo-hypoxic conditions that inflammatory mouse macrophages are subjected to. Moreover, the subtleties of NAD+ synthesis may also differ between inflammatory macrophages from the two species.…”