Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived from a given tissue, macrophages activate different functional programs to produce polarized macrophage populations responsible for inducing inflammation against microbes, removing cellular debris, and tissue repair. However, accumulating evidence has revealed that macrophage polarization is pivotal in the pathophysiology of metabolic syndromes and cancer, as well as in infectious and autoimmune diseases. Recent advances in transcriptomic and metabolomic studies have highlighted the link between metabolic rewiring of macrophages and their functional plasticity. These findings imply that metabolic adaption to their surrounding microenvironment instructs activation of macrophages with functionally distinct phenotypes, which in turn probably leads to the pathogenesis of a wide spectrum of diseases. In this review, we have introduced emerging concepts in immunometabolism with focus on the impact on functional activation of macrophages. Furthermore, we have discussed the implication of macrophage plasticity on the pathogenesis of metabolic syndromes and cancer, and how the disease microenvironment manipulates macrophage metabolism with regard to the pathophysiology.

Genetic characteristics were analysed for recent clinical isolates of methicillin-resistant and -susceptible Staphylococcus aureus (MRSA and MSSA respectively) in Kathmandu, Nepal. MRSA isolates harbouring Panton-Valentine leukocidin (PVL) genes were classified into ST1, ST22 and ST88 with SCCmec-IV and ST772 with SCCmec-V (Bengal Bay clone), while PVL-positive MSSA into ST22, ST30 and ST772. ST22 isolates (PVL-positive MRSA and MSSA, PVL-negative MRSA) possessed a variant of elastin binding protein gene (ebpS) with an internal deletion of 180 bp, which was similar to that reported for ST121 S. aureus previously outside Nepal. Phylogenetic analysis indicated that the ebpS variant in ST22 might have occurred independently of ST121 strains. This is the first report of ST772 PVL-positive MRSA in Nepal and detection of the deletion variant of ebpS in ST22 S. aureus.

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Citation: Kim SW, Kim H-I, Thapa B, Nuwromegbe S, Lee K. Critical role of mTORC2-Akt signaling in TGF-b1-induced myofibroblast differentiation of human pterygium fibroblasts. Invest Ophthalmol Vis Sci. 2019;60:82-92. https://doi.org/10.1167/iovs.18-25376PURPOSE. Profibrotic activation is essential for pterygium development. In this study, we investigated the role of the mechanistic target of rapamycin (mTOR) in regulating TGF-b1induced myofibroblastic responses in human pterygium fibroblasts (HPFs) and elucidated the relative contributions of mTOR signaling components. METHODS.HPFs were pretreated with the mTOR inhibitors rapamycin and Torin2, and TGF-b1induced expression of profibrotic markers, including a-smooth muscle actin (a-SMA) and fibronectin, was evaluated. RNA interference-based approaches targeting raptor and rictor, regulatory subunits of mTOR complex 1 (mTORC1) and 2 (mTORC2), respectively, were used to determine the impact of each mTOR complex on HPFs. The contractile phenotype of HPFs was assessed by a collagen gel contraction assay. RESULTS.The mTOR active-site inhibitor Torin2, which suppresses both mTORC1 and mTORC2 activity in HPFs, inhibited TGF-b1-induced expression of a-SMA and fibronectin. The allosteric inhibitor rapamycin only partially suppressed mTORC1 activity and exhibited a minimal effect on the induction of profibrotic markers. The induction of a-SMA and fibronectin in HPFs was abrogated by RNA interference-mediated knockdown of rictor but was only moderately affected by raptor knockdown. Akt inhibition mimicked the effect of Torin2 and rictor knockdown on myofibroblast differentiation of HPFs. mTOR inhibition potently reduced the contractile ability of HPFs in collagen gel contraction assays.CONCLUSIONS. This study found that mTOR signaling promoted profibrotic activation of HPFs and confirmed the importance of the mTORC2-Akt axis in TGF-b1-induced myofibroblast differentiation. Therefore, our study may open up new avenues for the development of novel therapeutic strategies involving targeting of mTOR signaling to treat pterygium.

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