MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis

Accumulation of macrophage"foam"cells,laden with cholesterol and cholesteryl ester,within the intima of large arteries,is a hallmark of early"fatty streak"lesions which can progress to complex,multicellular atheromatous plaques,involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response.Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway.Within the arterial intima,however,this mechanism is overwhelmed,leading to distinct changes in macrophage phenotype and inflammatory status.Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function,and in particular the importance of small non-coding micro-RNA(miRNA)sequences in this context.This review identifies some of the miRNA sequences which play a key role in regulating"foam"cell formation and atherogenesis,highlighting sequences involved in cholesterol accumulation,those influencing inflammation in sterol-loaded cells,and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.

Macrophage polarization in nerve injury： do Schwann cells play a role？

In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function – most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior.

Essential Gene(s) Targeted by Peptide Nucleic Acids Kills <i>Mycobacterium smegmatis</i>in Culture and in Infected Macrophages

Background: Antisense peptide nucleic acids (PNAs) exhibit growth inhibitory effects on bacteria by inhibiting the expression of essential genes and could be promising therapeutic agents for treating bacterial infections. A study was carried out to determine the efficacy of several antisense PNAs in inhibiting extracellular and intracellular growth of Mycobacterium smegmatis. Methods: Six PNAs obtained from a commercial supplier were tested to evaluate the inhibitory effect on bacterial growth by inhibiting the expression of the following essential genes: inhA (a fatty acid elongase), rpsL (ribosomal S12 protein), gyrA (DNA gyrase), pncA (pyrazinamidase), polA (DNA polymerase I) and rpoC (RNA polymerase β subunit) of M. smegmatis. Each PNA was tested at 20 μM, 10 μM, 5 μM and 2.5 μM concentrations to determine whether they caused a dose dependent killing of M. smegmatis cultured in Middlebrook 7H9 broth or in a J774A.1 murine macrophage cell line. Results: In Middlebrook broth, the strong growth inhibitory effect against M. smegmatis was observed by PNAs targeting the inhA and rpsL genes at all four concentrations. The PNAs targeting the pncA, polA and rpoC genes were found to exhibit strong growth inhibition against M. smegmatis but only at 20 μM concentration. No growth inhibition of M. smegmatis was seen in pure culture when treated with PNAs targeting gyrA and a mismatch PNA targeting dnaG (DNA primase). All six PNAs showed killing of M. smegmatis in J774A.1 macrophage cell line that were statistically significant (p < 0.05). Conclusion: It may be concluded from this study that PNAs could be potential therapeutics for mycobacterial infections.

Host immune cellular reactions in corneal neovascularization

Corneal neovascularization（CNV） is a global important cause of visual impairment. The immune mechanisms leading to corneal heme- and lymphangiogenesis have been extensively studied over the past years as more attempts were made to develop better prophylactic and therapeutic measures. This article aims to discuss immune cells of particular relevance to CNV, with a focus on macrophages, Th17 cells, dendritic cells and the underlying immunology of common pathologies involving neovascularization of the cornea. Hopefully, a thorough understanding of these topics would propel the efforts to halt the detrimental effects of CNV.

Effects of Andrographolide on the Activation of Mitogen Activated Protein Kinases and Nuclear Factor-κ B in Mouse Peritoneal Macrophage-derived Foam Cells

Objective： To observe the effect of andrographolide on the activation of mitogen-activated protein kinases （MAPKs） and expression of nuclear factor- kB （NF-kB） in macrophage foam cells. Methods： The mouse peritoneal macrophages were cultured in the media in the presence of oxidized low-density lipoprotein （ox-LDL）, ox-LDL＋andrographolide, or neither （control）. The phosphorylation of MAPK molecules （p38MAPK, JNK, ERK1/2） and the expressions of NK- kB p65 were examined by Western blot. Results： As compared with cells in the control group, the expressions of phospho-p38 and NF- kB p65 were increased in the cells cultured with either ox-LDL or ox-LDL＋andrographolide （P〈0.01）, but attenuated significantly in the presence of ox-LDL＋ andrographolide when compared with ox-LDL （P〈0.05）. The phospho-JNK increased in the presence of either ox-LDL or ox-LDL＋andrographolide when compared with control cells （P〈0.01）, but no significant difference existed between ox-LDL and ox-LDL＋andrographolide （P〉0.05）. The expression of phospho-ERK1/2 was increased in the presence of ox-LDL compared with the control cells （P〈0.01）, but no significant differences existed between the cells cultured in the presence of ox-LDL＋andrographolide and the control medium （P〉0.05）. Conclusions： Andrographolide could inhibit the activation of ERK1/2, p38MAPK and NK-kB induced by ox-LDL in macrophage foam cells, which might be one of its mechanisms in preventing atherosclerosis.

Pentoxifylline Inhibits Liver Fibrosis via Hedgehog Signaling Pathway

Infection of schistosomiasis japonica may eventually lead to liver fibrosis, and no effective antifibrotic therapies are available but liver transplantation. Hedgehog（HH） signaling pathway has been involved in the process and is a promising target for treating liver fibrosis. This study aimed to explore the effects of pentoxifylline（PTX） on liver fibrosis induced by schistosoma japonicum infection by inhibiting the HH signaling pathway. Phorbol12-myristate13-acetate（PMA） was used to induce human acute mononuclear leukemia cells THP-1 to differentiate into macrophages. The THP-1-derived macrophages were stimulated by soluble egg antigen（SEA）, and the culture supernatants were collected for detection of activation of macrophages. Cell Counting Kit-8（CCK-8） was used to detect the cytotoxicity of the culture supernatant and PTX on the LX-2 cells. The LX-2 cells were administered with activated culture supernatant from macrophages and（or） PTX to detect the transforming growth factor-β gene expression. The m RNA expression of shh and gli-1, key parts in HH signaling pathway, was detected. The m RNA expression of shh and gli-1 was increased in LX-2 cells treated with activated macrophages-derived culture supernatant, suggesting HH signaling pathway may play a key role in the activation process of hepatic stellate cells（HSCs）. The expression of these genes decreased in LX-2 cells co-cultured with both activated macrophages-derived culture supernatant and PTX, indicating PTX could suppress the activation process of HSCs. In conclusion, these data provide evidence that PTX prevents liver fibrogenesis in vitro by the suppression of HH signaling pathway.

A pH-responsive biomimetic drug delivery nanosystem for targeted chemo-photothermal therapy of tumors

Smart drug delivery nanosystem is significant for tumor treatments due to its possibility of temporally,spatially,and dose-controlled release.However,the therapeutic efficacy of drug delivery nanosystem is often compromised in cancer treatment as the enrichment of therapeutic agents in the reticuloendothelial system.Herein,doxorubicin(DOX)loaded biomimetic drug delivery nanosystem with macrophage cell membrane(MCM)camouflaged,MnFe_(2)O_(4)-DOX-MCM nanocube(NC),is developed for cancer treatment with tumor targeting,pH-stimuli drug release,and chemo-photothermal therapeutic effects.The nanosystem shows the capability of immune escape and enhanced cellular uptake of cancer cells due to the MCM decoration.Acid-labile bond between the MnFe2O4 NCs and DOX remains stable at physiological condition and release drugs immediately in response to the endo-/lysosome pH stimuli.Meanwhile,the photothermal effect of the nanosystem destroys tumor tissue,which further promotes chemotherapeutic efficacy.In vivo results demonstrate the tumor homing ability and produce a notable synergistic therapeutic effect of the NCs.Thus,biomimetic pH-responsive drug delivery nanosystem,MnFe_(2)O_(4)-DOX-MCM NCs,is an effective nanoplatform,which might be potential application for cancer synergistic treatment.

Inflammatory Changes in Paravertebral Sympathetic Ganglia in Two Rat Pain Models

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models： ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion （DRG）, which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability （but not spontaneous activity） measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.

Resolution of inflammation and repair after ischemic brain injury

After ischemic stroke, proinflammatory molecules known as danger-associated molecular patterns (DAMPs) originating from damaged brain cells recruit and activate immune cells (neutrophils, macrophages, lymphocytes) further eliciting innate and adaptive immunity. During the acute phase from day 1 to day 3 of the stroke onset, macrophages play a major role in the progression of inflammation, promoting the destruction of brain tissue. During the recovery phase, from day 3~4 to day 7 after stroke onset, infiltrating macrophages switch to repairing macrophages, which clear the DAMPs and promote tissue repair by producing neurotrophic factors. Adaptive immunity during the late or chronic phase (> day 7) of stroke has not been well investigated. Recent studies have also indicated that antigen-specific T cells, especially regulatory T cells (Tregs), play major roles in neural repair. This review focuses mainly on the resolution of inflammation and tissue repair by macrophages and Tregs.