Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage

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.

Methamphetamine and its immune-modulating effects

“…In astrocytes, METH was shown to increase IL-8 in a dose-dependent manner [62]. Other work has described a moderate IL-8 upregulation in the presence of METH on macrophages [17]. Similarly, macrophages treated with METH at 48 to 72 hours resulted in significant increase in IL-8; these findings, compared to macrophages treated with LPS alone showed higher IL-8 expression [25].…”

“…Similarly, the evaluation of METH in microglial cell (ESdM) activation showed an increased IL-10 production following 48-hr METH treatment [52]. In a comprehensive gene array overview, macrophages stimulated over a time-dependent METH dose showed considerable upregulation of IL-10 at 6 hours post METH exposure [17].…”

“…In healthy individuals, 90-95% of circulating monocytes are CD14+CD16-, whilst 5-10% are CD14+/CD16+ [23]. Macrophages secrete cytokines in response to external stimuli, which are involved in the recruitment of other immune cells to initiate a cascade of innate and adaptive immune responses [17]. In the presence of METH, macrophages secrete pro-inflammatory cytokines, interleukin-1 (IL-1) beta, IL-2, IL-6 and IL-8 [24] with IL-1 and IL-6 being significantly upregulated in the co-presence of bacterial lipopolysaccharide (LPS) [25].…”

“…METH has significant effects on both the innate and adaptive immune responses [12,15], with reported reductions in the numbers of natural killer (NK) cells and leukocytes [16]. In addition, macrophages stimulated by METH show increased levels of the pro-inflammatory cytokine TNF- [17][18][19]. METH causes decreased levels of dendritic cells (DCs) [20], impacting the adaptive immune system and rendering individuals susceptible to certain diseases and infections [16].…”

Secreted Metabolome of Human Macrophages Exposed to Methamphetamine

“…Thus, in this study, we were interested in how this secreted metabolome is affected when macrophages are exposed to the unfavorable environment caused by Meth 5–6 . Numerous publications provide evidence that functions of macrophages are susceptible to adverse effects of Meth 5, 7–11 .…”