Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.

Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects one-third of the global population. It can live within macrophages owning to its ability to arrest phagolysosome biogenesis. Autophagy has recently been identified as an effective way to control the intracellular mycobacteria by enhancing phagosome maturation. In the present study, we demonstrate a novel role of miR-155 in regulating the autophagy-mediated anti-mycobacterial response. Both in vivo and in vitro studies showed that miR-155 expression was significantly enhanced after mycobacterial infection. Forced expression of miR-155 accelerated the autophagic response in macrophages, thus promoting the maturation of mycobacterial phagosomes and decreasing the survival rate of intracellular mycobacteria, while transfection with miR-155 inhibitor increased mycobacterial survival. However, macrophage-mediated mycobacterial phagocytosis was not affected after miR-155 overexpression or inhibition. Furthermore, blocking autophagy with specific inhibitor 3-methyladenine or silencing of autophagy related gene 7 (Atg7) reduced the ability of miR-155 to promote autophagy and mycobacterial elimination. More importantly, our study demonstrated that miR-155 bound to the 3′-untranslated region of Ras homologue enriched in brain (Rheb), a negative regulator of autophagy, accelerated the process of autophagy and sequential killing of intracellular mycobacteria by suppressing Rheb expression. Our results reveal a novel role of miR-155 in regulating autophagy-mediated mycobacterial elimination by targeting Rheb, and provide potential targets for clinical treatment.

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Women's empowerment can be associated with undernutrition. Efforts to improve nutrition may benefit from empowerment initiatives that promote women's self-confidence and decision-making in Benin. However, additional qualitative and longitudinal research may enhance understanding of WE in the present area.

Citation: Sun M, Zhu M, Chen K, et al. TREM-2 promotes host resistance against Pseudomonas aeruginosa infection by suppressing corneal inflammation via a PI3K/Akt signaling pathway. Invest Ophthalmol Vis Sci. 2013;54:3451-3462. DOI:10.1167/ iovs.12-10938 PURPOSE. To explore the role of triggering receptor expressed on myeloid cells 2 (TREM-2) in Pseudomonas aeruginosa (PA) keratitis.METHODS. BALB/c mice were routinely infected with PA and evaluated at various postinfection time points for corneal expression of TREM-2, by real-time PCR, Western blot, and flow cytometry. Next, BALB/c and C57BL/6 mice were respectively treated with TREM-2 siRNA or agonistic anti-TREM-2 antibody, to determine the role of TREM-2 in PA keratitis. Bacterial load and neutrophil infiltration were tested by plate count and myeloperoxidase assay, respectively. Th1-/Th2-type and proinflammatory cytokine expression were tested by realtime PCR and ELISA after in vivo and in vitro silencing of TREM-2. Moreover, phosphorylated Akt levels were tested by Western blot in murine macrophages after treatment with agonistic anti-TREM-2 antibody. mRNA levels of proinflammatory cytokines were examined in murine macrophages after TREM-2 activation and lipopolysaccharide stimulation, following pretreatment with inhibitors for PI3K or Akt, to determine whether PI3K/Akt is required in TREM-2-mediated immune modulation. In addition, BALB/c mice were treated with wortmannin and analyzed for bacterial load and proinflammatory cytokine expression.RESULTS. TREM-2 expression was elevated in the infected BALB/c corneas at 3 or 5 days postinfection. Silencing of TREM-2 accelerated disease progression by enhancing bacterial load and corneal inflammation, whereas activation of TREM-2 promoted host resistance to PA keratitis. PI3K/Akt signaling is required in the TREM-2-mediated immune modulation, and inhibition of PI3K resulted in worsened disease after PA corneal infection.CONCLUSIONS. TREM-2 promoted host resistance to PA infection by suppressing corneal inflammation via activation of the PI3K/Akt pathway.

Triggering receptor expressed on myeloid cells 2 (TREM-2) is a cell surface receptor abundantly expressed on myeloid lineage cells such as macrophages and dendritic cells. It is reported that TREM-2 functions as an inflammatory inhibitor in macrophages and dendritic cells. However, the role of TREM-2 in bacterial killing remains unclear. This study explored the role of TREM-2 in bacterial eradication of Pseudomonas aeruginosa (PA), a Gram-negative bacterium which causes various opportunistic infections. Phagocytosis assay assessed by flow cytometry suggested that TREM-2 was not involved in the uptake of PA by macrophages, while bacterial plate count data showed that TREM-2 was required for macrophage-mediated intracellular killing of PA. Moreover, our results demonstrated that TREM-2 promoted macrophage killing by enhancing reactive oxygen species (ROS), but not nitric oxygen (NO) production. Treatment with N-acetylcysteine, a ROS scavenger, diminished the TREM-2-mediated intracellular killing of PA. To further investigate the underlined mechanisms of TREM-2-promoted bacterial killing, we examined the activation of downstream mitogen-activated protein kinases and PI3K/Akt pathway. Western blot data showed that silencing of TREM-2 inhibited phosphorylation of Akt, but not ERK, JNK or P38. In addition, pretreatment with PI3K active product PIP3 DiC16 reversed the elevation of intracellular bacterial load in TREM-2-silenced macrophages, while PI3K inhibitor wortmannin restored the decline of bacterial load in TREM-2-overexpressed macrophages. These data together suggested that the TREM-2-mediated bacterial killing is dependent on the activation of PI3K/Akt signalling, which may provide a better understanding of the host antibacterial immune defence.

miR-155 (microRNA-155) is an important noncoding RNA in regulating host inflammatory responses. However, its regulatory role in ocular infection remains unclear. Our study first explored the function of miR-155 in Pseudomonas aeruginosa-induced keratitis, one of the most common sight-threatening ocular diseases. We found that miR-155 expression was enhanced in human and mouse corneas after P. aeruginosa infection and was mainly expressed in macrophages but not neutrophils. In vivo studies demonstrated that miR-155 knockout mice displayed more resistance to P. aeruginosa keratitis, with a higher inducible nitric oxide synthase level and a lower bacterial burden. More importantly, in vitro data indicated that miR-155 suppressed the macrophage-mediated bacterial phagocytosis and intracellular killing of P. aeruginosa by targeting Rheb (Ras homolog enriched in brain). To the best of our knowledge, this is the first study to explore the role of miR-155 in bacterial keratitis, which may provide a promising target for clinical treatment of P. aeruginosa keratitis and other infectious diseases.

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