Abstract
Opioid drug abusers have a greater susceptibility to gram positive (Gram (+)) bacterial infections. However, the mechanism underlying opioid modulation of Gram (+) versus Gram (−) bacterial clearance has not been investigated. In this study, we show that opioid treatment resulted in reduced phagocytosis of Gram (+), when compared to Gram (−) bacteria. We further established that LPS priming of chronic morphine treated macrophages leads to potentiated phagocytosis and killing of both Gram (+) and Gram (−) bacteria in a P-38 MAP kinase dependent signaling pathway. In contrast, LTA priming lead to inhibition of both phagocytosis and bacterial killing. This study demonstrates for the first time the differential effects of TLR4 and TLR2 agonists on morphine induced inhibition of phagocytosis. Our results suggest that the incidence and severity of secondary infections with Gram (+) bacteria would be higher in opioid abusers.
Highlights
TLR2 and TLR4 are the most extensively studied members of the TLR family which recognizes bacterial products from Gram-positive bacteria, such as lipoteichoic acid (LTA), and Gram-negative bacteria, such as lipopolysaccharide (LPS), respectively
Considering current literature and observations that toll-like receptors signaling may be interacting with opioid receptors to modulate macrophage phagocytosis[20], the aim of this study is to examine the effects of activation of TLR2 and TLR4 by LTA and LPS respectively on morphine mediated inhibition of phagocytosis
In order to examine differential effects of gram positive and gram negative bacterial products on morphine induced inhibition of phagocytosis of Gram-positive and Gram-negative bacteria we examined the effects of lipoteichoic acid (LTA) a TLR2 ligand, and a lipopolysaccharide (LPS) a TLR4 ligand on phagocytosis
Summary
TLR2 and TLR4 are the most extensively studied members of the TLR family which recognizes bacterial products from Gram-positive bacteria, such as lipoteichoic acid (LTA), and Gram-negative bacteria, such as lipopolysaccharide (LPS), respectively. No studies have examined how TLR activation during chronic morphine treatment modulates phagocytosis. Considering current literature and observations that toll-like receptors signaling may be interacting with opioid receptors to modulate macrophage phagocytosis[20], the aim of this study is to examine the effects of activation of TLR2 and TLR4 by LTA and LPS respectively on morphine mediated inhibition of phagocytosis. Our results demonstrate that chronic morphine treatment inhibits phagocytosis of gram-positive bacteria more than gram-negative bacteria , which could account for increased incidence and severity of gram positive infections in chronic opioid users and abusers. Elucidation of mechanisms by which LPS and LTA modulates bacterial phagocytosis and clearance in the context of opioids will add to our understanding and treatment of infections in chronic opiate users and abusers
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