Dataset Information

A dopamine D1-like receptor agonist ameliorates stab wound-induced brain injury through its immunosuppressive effect

ABSTRACT: Traumatic brain injury (TBI) causes progressive nervous tissue degeneration long after the initial injury due to secondary neuroinflammatory reactions. G protein-coupled dopamine D1-like receptors, which elevate intracellular cAMP levels, have been shown to mediate the suppressive effects on lipopolysaccharide (LPS)-induced proinflammatory activation of microglia and macrophages. The present study investigated whether or not the D1-like receptor-specific agonist SKF-81297 (SKF) administered intraperitoneally once daily for 3 days starting 1 h after TBI could ameliorate TBI in a rat model of stab wounds in the forebrain. SKF reduced the volume of TBI-induced brain tissue loss, increased mobile activity, and ameliorated cognitive dysfunction two months after TBI. A single dose of SKF suppressed the expression of IL-1β and TNFα in brain tissue by reducing oxidative injury 24 h post-TBI. SKF decreased the energy metabolism of microglia, macrophages, and neutrophils in TBI brain. SKF prevented LPS-induced translocation of NFκB into the nuclei of primary cultured microglia. The agonist clenbuterol (CLB) for adrenergic β2 receptor, another Gs-linked GPCR, exerted comparable ameliorative effects in TBI model rats by suppressing neuroinflammation. In summary, SKF may exert anti-inflammatory effects by suppressing the NFB pathway through increasing cAMP similarly to CLB and also by decreasing energy metabolism of inflammatory cells, leading to amelioration of TBI-induced brain degeneration.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE298938 | GEO | 2026/03/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Traumatic brain injury (TBI) induces neuroinflammatory innate immune responses that plays roles in both worsening brain damage and facilitating functional recovery. A major goal is to understand the heterogeneity of the immune responses to TBI, and to precisely identify key components that impact functional outcomes. We previously demonstrated that genetically targeting Ccr2 in a mouse model of controlled cortical impact led to neuroprotection in TBI. Our current studies of TBI use single cell RNA sequencing of over 10,000 TBI ipsilateral brain leukocytes to examine the mechanisms associated with the observed benefit in Ccr2-/- mice by comparing gene expression in leukocyte subsets from Ccr2-/- mice to gene expression in C57BL/6 wild type mice. Unbiased clustering identified two monocyte subsets, Chil3hi Ly6Chi classical monocytes and Gpnmbhi Ly6Clo nonclassical monocytes, and nine microglia states in the ipsilateral TBI brain. Comparative analysis between the genotypes revealed that Ccr2-/- TBI mice contained reduced numbers of inflammatory macrophages. In TBI, we observed a subset of microglia highly expressing several type I interferon-stimulated genes (ISGs) and is designated as Irf7hi microglia. Notably, unbiased differential expression analysis detected a two-fold reduction in the type I interferon response in multiple Ccr2-/- TBI microglia subsets compared to wild type TBI microglia. Treatment post-injury with a human CCR2 (hCCR2) inhibitor, CCX872, in hCcr2 knock-in mice improved cognitive function post-TBI, and also correlated with reduced expression of a key ISG, Irf7. We identified and characterized macrophage and microglia subsets during acute TBI. Our data showed that a reduction in macrophage expansion in TBI by both genetic and pharmacological methods, improved TBI and correlated with a reduction in the type I IFN response. These data indicate that macrophage expansion co-directs a type IFN response in microglia, and that targeting macrophage expansion in the brain can alter the profile of microglia subsets and lead towards improved functional outcomes.

Project description:Background: Traumatic brain injury (TBI) is a growing and under-recognized public health threat with significant long-term complications suffered by its survivors. Monocytes are amongst the first immune cells to infiltrate the injured brain and have the ability to both foster wound repair and promote inflammation. Microglia, the resident innate immune cells in the brain, drive the long-term direction of the inflammatory response within the injured brain. Previously published data from our laboratory has shown that a brief course of peri-injury monocyte depletion attenuates long-term neurocognitive deficits and preserves white matter connectivity post-injury. Nonetheless, the role that monocytes play in directing the local inflammatory response to injury via crosstalk with microglia remains unknown. To this end, we hypothesized that infiltrating monocytes shape the long-term transcriptional response of microglia to TBI. Methods: We employed a 2x2 study design consisting of four experimental groups—TBI, sham, TBI with monocyte depletion, and TBI with sham monocyte depletion. Male C57BL/6 mice were randomly assigned to groups. Monocyte depletion and sham depletion were induced via intravenous injection of liposome-encapsulated clodronate versus naked liposomes 24 hour prior to TBI. Depletion was maintained via repeat injections on days 2 and 5. Monocyte depletion was confirmed via flow cytometry. TBI was induced using our established model of controlled cortical impact. BMice were euthanized on post-injury days 1, 7, 14, 30, and 60. Brains were harvested and microglia sorted via flow cytometry. The transcriptional response of microglia across groups and timepoints was assess via bulk RNA sequencing. Conclusion:These data shows that short-course of peri-injury depletion of peripheral monocytes may have a neuroprotective effect after TBI. While the mechanisms of this protection are multifactorial, alteration of the long-term transcriptional profile of microglia may, in part, be responsible for the observed improvements in motor coordination, learning, and memory. Identified pathways include inflammation, neuroplasticity and regeneration, and a neuroprotective heat shock response. These data warrant further investigation into possible therapeutic benefits of peri-injury immune modulation.Results:Monocyte-depleted mice demonstrated improvement in motor coordination, contextual and associative learning, and memory. These neurocognitive differences were associated with distinctly different microglial transcriptional profiles evident within the first 1-2 weeks post injury. In particular, microglia within the monocyte-depleted group showed distinct upregulation of pathways including synaptic signaling, regulation of neuron differentiation, and myeloid leukocyte activation as compared to those from Vehicle TBI groups. By 60 days post injury, microglia from the monocyte-depleted TBI group had upregulation of the heat shock protein transcripts as compared to microglia from the Vehicle TBI group.

Dataset Information

A dopamine D1-like receptor agonist ameliorates stab wound-induced brain injury through its immunosuppressive effect

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets