Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity

Abstract

Microglia continuously survey the brain parenchyma and actively shift status following stimulation. These processes demand a unique bioenergetic programme; however, little is known about the metabolic determinants in microglia. By mining large datasets and generating transgenic tools, here we show that hexokinase 2 (HK2), the most active isozyme associated with mitochondrial membrane, is selectively expressed in microglia in the brain. Genetic ablation of HK2 reduced microglial glycolytic flux and energy production, suppressed microglial repopulation, and attenuated microglial surveillance and damage-triggered migration in male mice. HK2 elevation is prominent in immune-challenged or disease-associated microglia. In ischaemic stroke models, however, HK2 deletion p ro mo ted n eu ro in fl am mation and potentiated cerebral damages. The enhanced inflammatory responses after HK2 ablation in microglia are associated with aberrant mitochondrial function and reactive oxygen species accumulation. Our study demonstrates that HK2 gates both glycolytic flux and mitochondrial activity to shape microglial functions, changes of which contribute to metabolic abnormalities and maladaptive inflammation in brain diseases.Metabolism has emerged as a key regulator in both innate and adaptive immunity 1 . Microglia, the primary immune cells and key guardians of brain activity in the brain, adopt different metabolic states in response to exogenous stimuli 2-4 . For example, pro-inflammatory microglia utilize aerobic glycolysis to promote synthesis of inflammatory cytokines, whereas immunomodulatory microglia in mice increase fatty acid metabolism to drive anti-inflammatory responses 2,3 . Moreover, metabolic dysfunction of microglia has been implicated in multiple diseases including Alzheimer's disease (AD) and chronic demyelination disease models [4][5][6] . Microglia deficient in triggering the receptor expressed on

HK2 in microglia and macrophages contribute to the development of neuropathic pain

“…The role of HK2 in inflammation regulation remains elusive. While some studies reported that inhibition of HK2 attenuates inflammation and alleviates pathogenesis of colitis and pulmonary arterial hypertension by inhibiting glycolysis (Hinrichsen et al, 2021; Liu et al, 2020), we found that Hk2 deletion in microglia potentiates inflammation and injury in a mouse model of ischemic stroke by impairing mitochondrial functions (Y. Hu et al, 2022). Here we show that Hk2 deletion in myeloid cells reduced inflammation in DRG and elicited analgesic effects.…”

“…To investigate whether HK2 levels are changed after SNI, we used a HK2‐reporter line, in which a P2A CreER ‐P2A‐tdTomato (tdT) cassette was inserted before the stop codon of HK2 (Figure 1a). The tdT fluorescence in this transgenic mouse line recapitulates the expression levels of HK2 in vivo (Hu et al, 2022), allowing us to temporally track the expression of HK2 after nerve injury. Since the increase in SDH microglia reaches a peak 7 days after nerve injury, we mainly focused our observation during the first week in SNI models (Kobiela Ketz et al, 2017).…”

“…Glycolytic metabolism plays an important role in neuroinflammation (Cheng et al, 2014; Cheng et al, 2016), and HK2, an important glycolytic regulator, contributed to the pathogenesis of various neural disorders such as Alzheimer's disease and cerebral ischemic injury (Hu et al, 2022; Leng et al, 2022; Li et al, 2018). Although it is well‐known that neuropathic pain is accompanied by prominent inflammatory responses in the injured SDH and DRG, whether HK2 is involved in neuropathic pain remains unknown.…”

“…Studies have shown that peripheral nerve injury led to significant increases in glucose utilization and metabolic rate in SDH (Mao, Hayes, et al, 1992; Mao, Price, et al, 1992). Accumulating evidence indicated that HK might be a key linker between glucose metabolism and inflammation (Everts et al, 2014; Y. Hu et al, 2022; Leng et al, 2022; Sundaram et al, 2022). Upregulated HK2 in spinal microglia and DRG macrophages suggest that these cells increase their glycolytic metabolism via elevated HK2, likely to regulate inflammatory responses after SNI.…”

“…We have recently identified that hexokinase 2 (HK2), the most active isozyme of HK, is highly enriched in microglia (Hu et al, 2022). HK2 is sensitive to microglial state and elevated in reactive microglia under diverse pathological conditions (Hu et al, 2022). Increased expression and activity of HK2 is associated with upregulated glycolytic flux (Bustamante et al, 2018; Perrin‐Cocon et al, 2018; Seki & Gaultier, 2017).…”