Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke

Chauhan, Anjali; Hudobenko, Jacob; Mamun, Abdullah Al; Koellhoffer, Edward C.; Patrizz, Anthony; Ritzel, Rodney M.; Ganesh, Bhanu Priya; McCullough, Louise D.

doi:10.1186/s12974-018-1188-3

Cited by 10 publications

(9 citation statements)

References 57 publications

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“…This study is the first evidence that shows the importance of peripheral MCs and their role in stroke in aged animals. Our group has previously shown that stroke leads to increased neuroinflammation in aged animals [35,36,56]. We have also shown that the gut is "inflamed" after stroke [35].…”

Section: Discussionmentioning

confidence: 93%

Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

Blasco

Chauhan

Honarpisheh

et al. 2020

J Neuroinflammation

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Background: Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation, and mast cells residing in the gut are a primary source of histamine. Methods: Stroke was induced in male C57BL/6 J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice; mice underwent MCAO surgery and were euthanized at 6 h, 24 h, and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice were associated with agerelated changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results: We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of gut mast cells and gut histamine receptor expression levels. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucinproducing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24-h post-stroke. Conclusion: An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

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Section: Discussionmentioning

confidence: 93%

Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

Blasco

Chauhan

Honarpisheh

et al. 2020

J Neuroinflammation

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“…The regulation of transforming growth factor βactivated kinase 1 (TAK1), which is involved in both innate and adaptive immune responses and has conflicting inflammatory effects depending on the cell type, plays a key role in monocyte infiltration into the injury site following ischemic stroke. TAK1 deletion leads to reduced monocyte infiltration, thereby improving outcomes after ischemic stroke (115). In addition, Werner et al demonstrated that CXC motif chemokine receptor 4 (CXCR4) deficiency diminishes monocyte infiltration and dampens the levels of pattern recognition and defense response gene expression in monocyte-derived macrophages at the ischemic injury site, resulting in deteriorated ischemic stroke outcomes.…”

Section: Monocyte-derived Macrophagesmentioning

confidence: 99%

Monocyte Transmodulation: The Next Novel Therapeutic Approach in Overcoming Ischemic Stroke?

et al. 2020

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The immune response following neuroinflammation is a vital element of ischemic stroke pathophysiology. After the onset of ischemic stroke, a specialized vasculature system that effectively protects central nervous system tissues from the invasion of blood cells and other macromolecules is broken down within minutes, thereby triggering the inflammation cascade, including the infiltration of peripheral blood leukocytes. In this series of processes, blood-derived monocytes have a significant effect on the outcome of ischemic stroke through neuroinflammatory responses. As neuroinflammation is a necessary and pivotal component of the reparative process after ischemic stroke, understanding the role of infiltrating monocytes in the modulation of inflammatory responses may offer a great opportunity to explore new therapies for ischemic stroke. In this review, we discuss and highlight the function and involvement of monocytes in the brain after ischemic injury, as well as their impact on tissue damage and repair.

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“…S6). TR4 acts in immunity, myelination, oligodendrocyte differentiation, learning and behavior [Chauhan et al, 2018; Zhang et al, 2018]. Thus, we ventured that rs75547282 may contribute to the risk of ASD by regulating the binding of the TIGD5 promoter region to TR4.…”

Section: Discussionmentioning

confidence: 91%

Comprehensive Integrative Analyses Identify TIGD5 rs75547282 as a Risk Variant for Autism Spectrum Disorder

Xie

et al. 2021

Autism Research

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Although recent genome‐wide association studies have identified risk loci that strongly associates with autism spectrum disorder (ASD), how to pinpoint the causal genes remains a challenge. We aimed to pinpoint the potential causal genes and explore the possible susceptibility and mechanism. A convergent functional genomics (CFG) method was used to prioritize the candidate genes by combining lines of evidence, including Sherlock analysis, spatio‐temporal expression patterns, expression analysis, protein–protein interactions, co‐expression and association with brain structure. A higher score in the CFG approach suggested that more evidence supported this gene as an ASD risk gene. We screened genes with higher CFG scores for candidate functional single nucleotide polymorphisms (SNPs). A genotyping experiment (602 ASD children and 604 healthy sex‐matched children) and the dual‐luciferase reporter gene assay were followed to validate the effects of SNPs. We identified three genes (MAPT, ZNF285, and TIGD5) as candidate causal genes using the CFG approach. The genotyping experiment showed that TIGD5 rs75547282 was associated with an increased risk of ASD under the dominant model (OR = 1.37, 95% CI = 1.09–1.72, P = 0.006) though the statistical power was limited (5.2%). The T allele of rs75547282 activated the expression of TIGD5 compared with the C allele in the dual‐luciferase reporter assay. Our study indicates that such comprehensive integrative analyses may be an effective way to explore promising ASD susceptibility variants and needs to be further investigated in future research. Genotyping experiments should, however, be based on a larger population sample to increase statistical power. Lay Summary We set out to pinpoint the potential causal genes of ASD and explore the possible susceptibility and mechanism by combining lines of evidence from different analyses. Our results show that TIGD5 rs75547282 is associated with the risk of ASD in the Han Chinese population. In addition, a similar framework to seek promising ASD risk variants could be further investigated in future research Autism Res 2021, 14: 631–644. © 2021 International Society for Autism Research and Wiley Periodicals LLC

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Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke

Cited by 10 publications

References 57 publications

Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

Monocyte Transmodulation: The Next Novel Therapeutic Approach in Overcoming Ischemic Stroke?

Comprehensive Integrative Analyses Identify TIGD5 rs75547282 as a Risk Variant for Autism Spectrum Disorder

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