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Comparing Effects of Transforming Growth Factor β1 on Microglia From Rat and Mouse: Transcriptional Profiles and
Starlee Lively1, Doris Lam1,2, Raymond Wong1,2
1Krembil Research Institute, Genes and Development Division, University Health Network, Toronto, ON, Canada.
Abstract:
The cytokine, transforming growth factor β1 (TGFβ1), is up-regulated after central nervous system (CNS) injuries or diseases involving microglial activation, and it has been proposed as a therapeutic agent for treating neuroinflammation. Microglia can produce and respond to TGFβ1. While rats and mice are commonly used for studying neuroinflammation, very few reports directly compare them. Such studies are important for improving pre-clinical studies and furthering translational progress in developing therapeutic interventions. After intracerebral hemorrhage (ICH) in the rat striatum, the TGFβ1 receptor was highly expressed on microglia/macrophages within the hematoma. We recently found species similarities and differences in response to either a pro-inflammatory (interferon-γ, IFN-γ, +tumor necrosis factor, TNF-α) or anti-inflammatory interleukin-4 (IL-4) stimulus. Here, we assessed whether rat and mouse microglia differ in their responses to TGFβ1. Microglia were isolated from Sprague-Dawley rats and C57BL/6 mice and treated with TGFβ1. We quantified changes in expression of >50 genes, in their morphology, proliferation, apoptosis and in three potassium channels that are considered therapeutic targets. Many inflammatory mediators, immune receptors and modulators showed species similarities, but notable differences included that, for some genes, only one species responded (e.g., Il4r, Il10, Tgfbr2, colony-stimulating factor receptor (Csf1r), Itgam, suppressor of cytokine signaling 1 (Socs1), toll-like receptors 4 (Tlr4), P2rx7, P2ry12), and opposite responses were seen for others (Tgfb1, Myc, Ifngr1). In rat only, TGFβ1 affected microglial morphology and proliferation, but there was no apoptosis in either species. In both species, TGFβ1 dramatically increased Kv1.3 channel expression and current (no effects on Kir2.1). KCa3.1 showed opposite species responses: the current was low in unstimulated rat microglia and greatly increased by TGFβ1 but higher in control mouse cells and decreased by TGFβ1. Finally, we compared TGFβ1 and IL10 (often considered similar anti-inflammatory stimuli) and found many different responses in both species. Overall, the numerous species differences should be considered when characterizing neuroinflammation and microglial activation in vitro and in vivo, and when targeting potassium channels.
Insights
Rat and mouse microglia exhibit significant species-specific differences in their response to transforming growth factor β1 (TGFβ1), impacting gene expression and ion channel activity. These variations are crucial for understanding neuroinflammation and developing targeted therapies.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Transforming growth factor β1 (TGFβ1) is implicated in central nervous system (CNS) injuries and neuroinflammation, with microglia playing a key role.
- TGFβ1 is proposed as a therapeutic agent for neuroinflammation, yet direct comparisons of rat and mouse microglial responses are scarce.
- Understanding species-specific differences is vital for improving preclinical studies and advancing translational therapeutic development.
Purpose of the Study:
- To investigate and compare the responses of rat and mouse microglia to TGFβ1 stimulation.
- To analyze species-specific alterations in gene expression, cell morphology, proliferation, apoptosis, and potassium channel activity.
Main Methods:
- Isolation and treatment of microglia from Sprague-Dawley rats and C57BL/6 mice with TGFβ1.
- Quantification of gene expression changes (>50 genes), microglial morphology, proliferation, and apoptosis.
- Assessment of Kv1.3, Kir2.1, and KCa3.1 potassium channel expression and function.
Main Results:
- Significant species-specific differences observed in gene expression, with some genes responding only in one species or showing opposite responses.
- TGFβ1 influenced microglial morphology and proliferation in rats but not in mice; no apoptosis was observed in either species.
- TGFβ1 increased Kv1.3 channel expression and current in both species, but induced opposite effects on KCa3.1 currents, with distinct responses compared to IL-10.
Conclusions:
- Rat and mouse microglia display numerous, significant differences in their molecular and functional responses to TGFβ1.
- These species-specific variations necessitate careful consideration in the characterization of neuroinflammation and microglial activation.
- The findings highlight the importance of accounting for species differences when developing therapeutic strategies targeting microglia and potassium channels.
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