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Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage
Ariel Burns1, Pawel Ciborowski1
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
Abstract:
Recent studies show that methamphetamine (Meth) use leads to higher susceptibility to and progression of infections, which suggests impairment of the immune system. The first line of defense against infections is the innate immune system and the macrophage is a key player in preventing and fighting infections. So we profiled cytokines over time in Meth treated THP-1 cells, as a human macrophage model, at a relevant concentration using high throughput screening to find a signaling target. We showed that after a single exposure, the effect of Meth on macrophage cytokine production was rapid and time dependent and shifted the balance of expression of cytokines to pro-inflammatory. Our results were analogous to previous reports in that Meth up-regulates TNF-α and IL-8 after two hours of exposure. However, global screening led to the novel identification of CXCL16, CXCL1 and many other up-regulated cytokines. We also showed CCL7 as the most down-regulated chemokine due to Meth exposure, which led us to hypothesize that Meth dysregulates the MyD88-dependent Toll-like receptor 9 (TLR9) signaling pathway. In conclusion, altered cytokine expression in macrophages suggests it could lead to a suppressed innate immunity in people who use Meth.
Insights
Methamphetamine (Meth) use rapidly alters macrophage cytokine production, increasing pro-inflammatory signals and potentially suppressing innate immunity. This study identifies novel cytokine targets for understanding Meth
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Methamphetamine (Meth) use is linked to increased infection susceptibility, suggesting immune system impairment.
- Macrophages are crucial innate immune cells involved in fighting infections.
- Understanding Meth's impact on macrophage function is vital for public health.
Purpose of the Study:
- To profile cytokine production in a human macrophage model (THP-1 cells) following Meth exposure.
- To identify specific signaling pathways and cytokines affected by Meth.
- To elucidate the mechanisms by which Meth may suppress innate immunity.
Main Methods:
- THP-1 cells, a human macrophage model, were treated with Meth at a relevant concentration.
- Cytokine expression was profiled over time using high-throughput screening.
- Analysis focused on identifying rapid, time-dependent changes in cytokine production.
Main Results:
- Meth exposure rapidly and time-dependently shifted macrophage cytokine production towards a pro-inflammatory profile.
- Confirmed upregulation of TNF-α and IL-8, and identified novel upregulated cytokines including CXCL16 and CXCL1.
- CCL7 was identified as the most significantly downregulated chemokine, suggesting dysregulation of the MyD88-dependent TLR9 pathway.
Conclusions:
- Methamphetamine significantly alters macrophage cytokine expression, impacting innate immune responses.
- Novel cytokines like CXCL16, CXCL1, and CCL7 are identified as key players in Meth-induced immune modulation.
- Altered cytokine profiles suggest a potential mechanism for suppressed innate immunity in individuals using Meth.
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