25 research outputs found
Toll-Like Receptor 9 Is Required for Opioid-Induced Microglia Apoptosis
Opioids have been widely applied in clinics as one of the most potent pain
relievers for centuries, but their abuse has deleterious physiological effects
beyond addiction. However, the underlying mechanism by which microglia in
response to opioids remains largely unknown. Here we show that morphine induces
the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity
and inflammation. Interestingly, TLR9 deficiency significantly inhibited
morphine-induced apoptosis in microglia. Similar results were obtained when
endogenous TLR9 expression was suppressed by the TLR9 inhibitor CpGODN.
Inhibition of p38 MAPK by its specific inhibitor SB203580 attenuated
morphine-induced microglia apoptosis in wild type microglia. Morphine caused a
dramatic decrease in Bcl-2 level but increase in Bax level in wild type
microglia, but not in TLR9 deficient microglia. In addition, morphine treatment
failed to induce an increased levels of phosphorylated p38 MAPK and MAP kinase
kinase 3/6 (MKK3/6), the upstream MAPK kinase of p38 MAPK, in either TLR9
deficient or µ-opioid receptor (µOR) deficient primary microglia,
suggesting an involvement of MAPK and µOR in morphine-mediated TLR9
signaling. Moreover, morphine-induced TLR9 expression and microglia apoptosis
appears to require μOR. Collectively, these results reveal that opioids
prime microglia to undergo apoptosis through TLR9 and µOR as well. Taken
together, our data suggest that inhibition of TLR9 and/or blockage of µOR
is capable of preventing opioid-induced brain damage
Liver immunology and its role in inflammation and homeostasis
The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear ‘dangerous’ stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease