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Updated: Jan 20, 2026
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
INPP5D Upregulation by Minocycline Mitigates Sepsis-Associated Neuroinflammation and Neuronal Dysfunction Via
Yu-Jing Li1, Xiu Zhang2, Jing-Nan Fu3
1Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Abstract:
Sepsis-associated neuroinflammation contributes to long-term neurological deficits, but therapeutic strategies remain limited. Here, we demonstrate that minocycline (Mino) mitigates sepsis-induced neuroinjury by upregulating inositol polyphosphate-5-phosphatase D (INPP5D), thereby suppressing microglia-mediated central amygdala (CeA) neuronal hyperactivation. In a cecal ligation and puncture (CLP)-induced septic mouse model, Mino treatment improved behavioral deficits and reduced neuroinflammation. Multi-omics analyses identified INPP5D as a critical downstream effector of Mino's neuroprotection. In vitro, Mino enhanced INPP5D expression in microglia, concurrently inhibiting pro-inflammatory activation, promoting autophagy, restoring mitochondrial function, and augmenting antioxidant responses. Microglia-neuron co-culture experiments revealed that Mino-dependent INPP5D upregulation attenuated CeA neuronal hyperexcitability and dendritic spine loss. Crucially, in vivo silencing of INPP5D or autophagy blockade abolished Mino's protective effects, confirming the INPP5D-autophagy axis as indispensable for neuroprotection. Our findings unveil a novel mechanism whereby Mino rescues sepsis-induced neuroinjury via INPP5D-mediated modulation of microglial activation and CeA neuronal dysfunction, offering a promising therapeutic target for sepsis-associated encephalopathy.
Insights
Minocycline (Mino) protects against sepsis-induced brain injury by increasing INPP5D, which calms overactive brain cells. This discovery offers a new therapeutic approach for sepsis-associated encephalopathy.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Sepsis-induced neuroinflammation leads to lasting neurological damage.
- Current treatments for sepsis-associated encephalopathy are limited.
Purpose of the Study:
- To investigate the neuroprotective mechanisms of minocycline (Mino) in sepsis.
- To identify key molecular targets of Mino's therapeutic effects.
Main Methods:
- Cecal ligation and puncture (CLP) sepsis model in mice.
- Minocycline treatment and in vivo/in vitro assays.
- Multi-omics analysis, microglia-neuron co-cultures, gene silencing, and autophagy blockade.
Main Results:
- Minocycline treatment improved behavioral deficits and reduced neuroinflammation in septic mice.
- INPP5D was identified as a critical downstream target of minocycline's neuroprotective effects.
- Minocycline upregulated INPP5D in microglia, suppressing inflammation, enhancing autophagy, and restoring mitochondrial function, which protected neurons.
Conclusions:
- Minocycline exerts neuroprotection against sepsis-induced injury through the INPP5D-autophagy pathway.
- Upregulation of INPP5D in microglia is key to mitigating neuroinflammation and neuronal dysfunction.
- This pathway presents a novel therapeutic target for sepsis-associated encephalopathy.
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