Microglial response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice after systemic
Inge C M Hoogland1, Jutka Yik1, Dunja Westhoff1
1Department of Neurology, Amsterdam University Medical Centres, Location Academic Medical Centre, Amsterdam Neuroscience, University of Amsterdam, PO Box 22660, 1100DD Amsterdam, The Netherlands.
Background:
Systemic infection is an important risk factor for delirium, associated with neurodegeneration and subsequent cognitive impairment in older people. Microglial cell response is a known key player in this process and we hypothesize that the triggering receptor expressed on myeloid cells 2 (TREM2) plays an important role in the regulation of this response.
Methods:
8- to 10-week old male wild-type (WT) and TREM2 knock-out (Trem2-/-) mice were intraperitoneally inoculated with live Escherichia coli (E. coli) or saline. After inoculation, all mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h and were sacrificed after 2 and 3 days. Microglial response was determined by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry. mRNA expression of pro- and anti-inflammatory mediators was measured to quantify the inflammatory response.
Results:
We observed increased Iba-1 positive cells number in thalamus of Trem2-/- mice at 3d after inoculation compared to WT mice (mean 120 cell/mm2 [SD 8] vs 105 cell/mm2 [SD 11]; p = 0.03). Flow cytometry showed no differences in forward scatter or expression of CD11b, CD45 and CD14 between WT and Trem2-/- mice. The brain mRNA expression levels of tumor necrosis factor alpha (TNF-α) of Trem2-/- mice at 2d were higher compared to WT mice (p = 0.003). Higher mRNA expression of interleukin 1 beta (IL-1β), Iba-1, CD11b and mitogen-activated protein kinase 1 (MAPK-1) was found in brain of WT mice at 2d compared to Trem2-/- mice (respectively p = 0.02; p = 0.001; p = 0.03 and p = 0.02). In spleen there were no differences in inflammatory mediators, between WT and Trem2-/- mice.
Interpretation:
Although the loss of function of TREM2 during systemic infection led to an increased number of activated microglia in the thalamus, we did not observe a consistent increase in expression of inflammatory genes in the brain. The role of TREM2 in the neuro-inflammatory response following systemic infection therefore appears to be limited.
Insights
Systemic infection increases microglial activation in the brain, but the absence of triggering receptor expressed on myeloid cells 2 (TREM2) did not consistently alter inflammatory gene expression. TREM2
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Systemic infections are linked to neurodegeneration and cognitive decline in older adults.
- Microglial cell activation is a key process in infection-induced neuroinflammation.
- The role of TREM2 in regulating microglial response during systemic infection is not fully understood.
Purpose of the Study:
- To investigate the role of TREM2 in microglial cell response and neuroinflammation following systemic infection.
- To determine if TREM2 deficiency impacts the inflammatory gene expression in the brain and spleen after E. coli inoculation.
Main Methods:
- Wild-type (WT) and TREM2 knock-out (Trem2-/-) mice were inoculated with Escherichia coli (E. coli).
- Microglial activation was assessed using Iba-1 immunohistochemistry and flow cytometry.
- Brain and spleen mRNA levels of pro- and anti-inflammatory mediators were quantified.
Main Results:
- TREM2 deficiency led to increased Iba-1 positive cells in the thalamus 3 days post-infection.
- No significant differences in microglial surface markers (CD11b, CD45, CD14) were observed between groups.
- While TNF-α was higher in TREM2-/- mice, IL-1β, Iba-1, CD11b, and MAPK-1 were higher in WT mice, indicating a complex inflammatory response.
Conclusions:
- Loss of TREM2 function during systemic infection increases microglial activation in the thalamus.
- The study did not find a consistent increase in inflammatory gene expression in the brain of TREM2 deficient mice.
- The role of TREM2 in the neuroinflammatory response to systemic infection appears limited.
