Aging reprograms microglia toward an inflammasome-linked response to traumatic brain injury
Josh M. Morganti, Adam D. Bachstetter
Josh M. Morganti, Adam D. Bachstetter
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Commentary

Aging reprograms microglia toward an inflammasome-linked response to traumatic brain injury

Abstract

Traumatic brain injury (TBI) disproportionately kills and disables older adults, yet the biology driving this vulnerability remains unresolved. In this issue of the JCI, Lu et al. combined single-cell transcriptomics, metabolomics, and chromatin profiling in mice, validated in human TBI tissue, to define an age-dependent microglial dichotomy. They report that an NLRP3+/IL-1β–linked state dominates the aged brain, while a Lysozyme+/Lyz2+ state predominates in the young. Microglia-targeted perturbation of NLRP3 and ELF1 each shifted the balance and improved survival in mouse models of TBI, and the repurposed drug Imeglimin improved outcomes in these models, confirming that this pathway is druggable. By connecting NLRP3 inflammasome dominance, ELF1-driven transcription, and glycolytic reprogramming to the loss of a protective Lyz2+ response, this work converts age from a clinical risk factor to a set of druggable microglial targets.

Authors

Josh M. Morganti, Adam D. Bachstetter

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Figure 1

Aging redirects the post-TBI microglial response toward an inflammasome-linked state with distinct metabolic, chromatin, and transcriptional features.

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Aging redirects the post-TBI microglial response toward an inflammasome-...
Lu et al. (11) used a model of TBI and compared outcomes in young and aged mice. Microglial responses to injury diverged by age, with young adult mice preferentially mounting a Lysozyme/Lyz2+ response and aged adult mice preferentially developing an NLRP3+/IL-1β+ state. (A) In young injured brains, microglia were enriched for a Lysozyme/Lyz2+ state, characterized by lysosomal and phagocytic gene programs (Lyz2, Cst7, Spp1), partial concordance with DAM, and reliance on oxidative metabolism. (B) In aged injured brains, microglia were enriched for an NLRP3+/IL-1β+ inflammasome-linked state marked by inflammatory genes (Nlrp3, Il1b, Casp1), a glycolytic shift, increased chromatin accessibility at inflammatory and senescence-associated loci (Nlrp3, Casp1, Il1b, Il18, Cdkn1a, Cdkn2a), and an ELF1-associated transcriptional program. (C) In young mice, microglial Lyz2 deletion worsened neurological outcome following TBI, as measured by the modified Neurological Severity Score (mNNS), supporting a beneficial or at least nonharmful role for the Lysozyme+/Lyz2+ state. (D) In aged mice, microglial Nlrp3 deletion, microglia-selective Elf1 ablation, or treatment with the oxidative phosphorylation inhibitor Imeglimin each shifted the response away from the NLRP3+ state and improved outcome. Moreover, ELF1 loss and Imeglimin also normalized metabolic readouts in microglial cell systems. Together, these findings support a model in which aging redirects the post-TBI microglial response away from a reparative Lysozyme+/Lyz2+ program and toward a maladaptive inflammasome-linked state.