ABSTRACT
Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line with these findings, the innate immune responses required for clearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL's pro-inflammatory activity supports proper functioning of macrophage immune responses.
Subject(s)
Cholesterol/metabolism , Inflammation/metabolism , Inflammation/pathology , Lipoproteins, HDL/pharmacology , Macrophages/metabolism , Macrophages/pathology , Signal Transduction/drug effects , Animals , Base Sequence , Biological Transport/drug effects , Cells, Cultured , Humans , Interferon Regulatory Factor-1/metabolism , Membrane Microdomains/drug effects , Membrane Microdomains/metabolism , Mice , Mice, Inbred C57BL , Models, Biological , NF-kappa B/metabolism , Protein Kinase C/metabolism , Respiratory Tract Infections/metabolism , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/pathology , STAT1 Transcription Factor/metabolism , Toll-Like Receptors/metabolismABSTRACT
Endocannabinoids are potent regulators of synaptic strength. They are generally thought to modify neurotransmitter release through retrograde activation of presynaptic type 1 cannabinoid receptors (CB1Rs). In the cerebellar cortex, CB1Rs regulate several forms of synaptic plasticity at synapses onto Purkinje cells, including presynaptically expressed short-term plasticity and, somewhat paradoxically, a postsynaptic form of long-term depression (LTD). Here we have generated mice in which CB1Rs were selectively eliminated from cerebellar granule cells, whose axons form parallel fibers. We find that in these mice, endocannabinoid-dependent short-term plasticity is eliminated at parallel fiber, but not inhibitory interneuron, synapses onto Purkinje cells. Further, parallel fiber LTD is not observed in these mice, indicating that presynaptic CB1Rs regulate long-term plasticity at this synapse.
