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Harpin proteins produced by plant-pathogenic Gram-negative bacteria are the venerable player in regulating bacterial virulence and inducing plant growth and defenses. A major gap in these effects is plant sensing linked to cellular responses, and plant sensor for harpin Hpa1 from rice bacterial blight pathogen points to plasma membrane intrinsic protein (PIP). Here we show that Arabidopsis AtPIP1;4 is a plasma membrane sensor of Hpa1 and plays a dual role in plasma membrane permeability of CO2 and H2O. In particular, AtPIP1;4 mediates CO2 transport with a substantial contribute to photosynthesis and further increases this function upon interacting with Hpa1 at the plasma membrane. As a result, leaf photosynthesis rates are increased and the plant growth is enhanced in contrast to the normal process without Hpa1-AtPIP1;4 interaction. Our findings demonstrate the first case that plant sensing of a bacterial harpin protein is connected with photosynthetic physiology to regulate plant growth.

BackgroundNintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear.MethodsHuman monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin.ResultsHuman fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects.ConclusionsThese results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0654-2) contains supplementary material, which is available to authorized users.

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AMP-activated protein kinase (AMPK) is essential for maintaining energy balance and has a crucial role in various inflammatory pathways. In this study, AMPK levels positively correlated with many inflammatory indexes in rheumatoid arthritis (RA) patients, especially in the affected synovium. In RA sera, a positive correlation between phosphorylated (p-)AMPK-a1 levels and DAS28 (disease activity score 28) activity (r = 0.270, p < 0.0001) was found. Similarly, a positive correlation was observed between AMPK-a1 and tumor necrosis factor a (TNF-a) levels (r = 0.460, p = 0.0002). Differentially expressed genes between osteoarthritis (OA) and RA synovium from NCBI GEO profiles and our RNA sequencing data suggested activation of metabolic pathways specific to RA-fibroblast-like synoviocytes (FLSs). AMPK-a1 was highly expressed in the synovium of RA but not OA patients. An AMPK activator, metformin, inhibited FLS proliferation at higher but not lower concentrations, whereas the inhibitor dorsomorphin promoted the proliferation of RA-FLSs. Interestingly, both metformin and dorsomorphin inhibited the migration of RA-FLSs. After metformin treatment, expression of interleukin 6 (IL-6), TNF-a, and IL-1b were significantly downregulated in RA-FLSs; however, increased expression of p-AMPK-a1, protein kinase A (PKA)-a1, and HAPLN1 (hyaluronan and proteoglycan link protein 1) was observed. Increased levels of HAPLN1 in RA-FLSs by an AMPK activator could potentially be beneficial in protecting the joints. Hence, our results demonstrate the potential of an AMPK activator as a therapeutic for RA.