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1.
Am J Physiol Endocrinol Metab ; 327(1): E55-E68, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38717364

ABSTRACT

Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only inhibits de novo synthesis of cholesterol but also isoprenoids that are involved in prenylation, the posttranslational lipid modification of proteins. The immunomodulatory effects of statins are broad and often conflicting. Previous work demonstrated that statins increased survival and inhibited myeloid cell trafficking in a murine model of sepsis, but the exact mechanisms underlying this phenomenon were unclear. Herein, we investigated the role of prenylation in chemoattractant responses. We found that simvastatin treatment abolished chemoattractant responses induced by stimulation by C5a and FMLP. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to both chemoattractants was dependent on geranylgeranylation. Proteomic analysis of C15AlkOPP-prenylated proteins identified several geranylgeranylated proteins involved in chemoattractant responses, including RHOA, RAC1, CDC42, and GNG2. Chemoattractant responses in THP-1 human macrophages were also geranylgeranylation dependent. These studies provide data that help clarify paradoxical findings on the immunomodulatory effects of statins. Furthermore, they establish the role of geranylgeranylation in mediating the morphological response to chemoattractant C5a.NEW & NOTEWORTHY The immunomodulatory effect of prenylation is ill-defined. We investigated the role of prenylation on the chemoattractant response to C5a. Simvastatin treatment inhibits the cytoskeletal remodeling associated with a chemotactic response. We showed that the chemoattractant response to C5a was dependent on geranylgeranylation, and proteomic analysis identified several geranylgeranylated proteins that are involved in C5a receptor signaling and cytoskeletal remodeling. Furthermore, they establish the role of geranylgeranylation in mediating the response to chemoattractant C5a.


Subject(s)
Polyisoprenyl Phosphates , Polyisoprenyl Phosphates/pharmacology , Polyisoprenyl Phosphates/metabolism , Humans , Simvastatin/pharmacology , Chemotactic Factors/pharmacology , Chemotactic Factors/metabolism , Phagocytes/drug effects , Phagocytes/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Complement C5a/metabolism , Protein Prenylation/drug effects , Animals , Mice , Sesquiterpenes
2.
Immunobiology ; 228(4): 152411, 2023 07.
Article in English | MEDLINE | ID: mdl-37329824

ABSTRACT

Cross sectional studies have shown that statin-users have improved odds of surviving severe sepsis. Meanwhile controlled clinical trials failed to demonstrate improved sepsis survival with acute statin administration following hospitalization. Here, a lethal murine peritoneal lipopolysaccharide (LPS) endotoxemia model was used to assess the efficacy of chronic versus acute simvastatin on survival. Mirroring clinical observations, chronic but not acute treatment with simvastatin significantly increased survival. At a pre-mortality time point in LPS-treated mice, chronic simvastatin suppressed granulocyte trafficking in to the lungs and peritoneum without otherwise suppressing emergency myelopoiesis, myeloid cells in circulation, or inflammatory cytokines. Chronic simvastatin treatment significantly downregulated inflammatory chemokine gene signature in the lungs of LPS-treated mice. Thus, it was unclear if simvastatin was inhibiting granulocyte chemotaxis in a cell intrinsic or extrinsic manner. Adoptive transfer of fluorescently labeled granulocytes from statin and vehicle treated mice into LPS-treated mice showed that simvastatin inhibited lung-granulocyte trafficking in a cell intrinsic manner. Congruent with this, chemotaxis experiments using in vitro macrophages and ex vivo granulocytes demonstrated that simvastatin inhibited chemotaxis in a cell-intrinsic manner. Collectively, chronic but not acute simvastatin treatment improved survival in murine endotoxemia, and this was associated with cell-intrinsic inhibition of granulocyte chemotaxis.


Subject(s)
Endotoxemia , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Mice , Animals , Simvastatin/pharmacology , Simvastatin/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Endotoxemia/drug therapy , Lipopolysaccharides , Cross-Sectional Studies , Granulocytes
3.
Brain Behav Immun ; 80: 763-776, 2019 08.
Article in English | MEDLINE | ID: mdl-31108171

ABSTRACT

Acute stressors can induce fear and physiologic responses that prepare the body to protect from danger. A key component of this response is immune system readiness. In particular, inflammasome activation appears critical to linking stress to the immune system. Here, we show that a novel combination of handling procedures used regularly in mouse research impairs novel object recognition (NOR) and activates caspase-1 in the amygdala. In male mice, this handling-stress paradigm combined weighing, scruffing and sham abdominal injection once per hr. While one round of weigh/scruff/needle-stick had no impact on NOR, two rounds compromised NOR without impacting location memory or anxiety-like behaviors. Caspase-1 knockout (KO), IL-1 receptor 1 (IL-1R1) KO and IL-1 receptor antagonist (IL-RA)-administered mice were resistant to handling stress-induced loss of NOR. In addition, examination of the brain showed that handling stress increased caspase-1 activity 85% in the amygdala without impacting hippocampal caspase-1 activity. To delineate danger signals relevant to handling stress, caffeine-administered and adenosine 2A receptor (A2AR) KO mice were tested and found resistant to impaired learning and caspase-1 activation. Finally, mice treated with the ß-adrenergic receptor antagonist, propranolol, were resistant to handling stress-induced loss of NOR and caspase-1 activation. Taken together, these results indicate that handling stress-induced impairment of object learning is reliant on a pathway requiring A2AR-dependent activation of caspase-1 in the amygdala that appears contingent on ß-adrenergic receptor functionality.


Subject(s)
Adenosine/metabolism , Caspase 1/metabolism , Learning/physiology , Stress, Psychological/metabolism , Adenosine/pharmacology , Amygdala/metabolism , Animals , Anxiety , Brain/metabolism , Enzyme Activation , Fear/physiology , Hippocampus/metabolism , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Male , Memory/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, Interleukin-1 Type I/genetics , Receptors, Interleukin-1 Type I/metabolism , Receptors, Purinergic P1/metabolism , Signal Transduction/drug effects
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