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Infiltrating Anti-Inflammatory Monocytes Modulate Microglial Activation through TLR4-IFN Dependent Pathways following Traumatic Brain Injury

J Trauma Acute Care Surg. 2023 Jan 5. doi: 10.1097/TA.0000000000003858. Online ahead of print.

ABSTRACT

BACKGROUND: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in the pediatric population. Microglia and infiltrating monocyte-derived macrophages (MDMs) are crucial immune cells that modulate the neuroinflammatory response following TBI. Using C34, a novel pharmacologic TLR4 inhibitor, we investigated the intricate interactions between these cells in a murine TBI model.

METHODS: A murine controlled cortical impact (CCI) model was utilized, and the results were analyzed on post-injury days (PID) 1, 7, 28 and 35. The experimental groups are (1) Sham C57BL/6 wild-type (WT), (2) TBI WT, (3) Sham WT + C34 and (4) TBI WT + C34. Real-time PCR (qRT-PCR) was used to quantify gene expression associated with microglial activation, apoptotic pathways and type 1 interferon pathway. Flow cytometry was used to isolate microglia and infiltrating monocytes. Brain lesion volumes were assessed using MRI. Last, neurocognitive outcomes were evaluated using the Morris Water Maze (MWM) test. Student’s T-test and One-way ANOVA were used for statistical analysis with significance achieved when p < 0.05.

RESULTS: TLR4 inhibition leads to improved neurological sequela post-TBI, possibly due to an increase in infiltrating anti-inflammatory monocytes and a decrease in IRF7 during acute inflammation, followed by a reduction in apoptosis and M2 microglial expression during chronic inflammation.

CONCLUSIONS: TLR4 inhibition with C34 skews infiltrating monocytes towards an anti-inflammatory phenotype leading to enhanced neurocognitive outcomes. Moreover, although M2 microglia have been consistently shown as inducers of neuroprotection, our results clearly demonstrate their detrimental role during the chronic phases of healing post-TBI.Study type: Original Research (Basic Science).

PMID:36598757 | DOI:10.1097/TA.0000000000003858

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