Highlights d The transcription factor Spic restrains inflammatory responses in macrophages d Spic promotes the expression of the iron exporter ferroportin in activated macrophages d NF-kB activity is required for the expression of Spic in activated macrophages d Interferon-gamma suppresses Spic expression in activated macrophages

The recruitment of myeloid cells to the lung is of utmost importance for the elimination of invading pathogens. We investigated the Streptococcus pneumoniae-dependent induction mechanism of KLF4 in macrophages as a potential regulator of the macrophage immune response. We demonstrated that only viable pneumococci, which have direct contact to the host cells and release LytA-dependent DNA, induced KLF4. Exogenous supplementation of pneumococcal, other bacterial, eukaryotic foreign (human) or self (mouse) DNA to autolysis-deficient pneumococci restored (at least in part) pneumococci-related KLF4 induction. Experiments using TLR9, TRIF and MyD88 knockout macrophages revealed that TLR9, TRIF and MyD88 were partly involved in the S. pneumoniae-induced KLF4 expression. BMMs missing important DNA receptor related molecules (ASC−/−, STING−/−) showed no differences in pneumococci-related KLF4 expression. Similar results were observed with IFNAR−/− BMMs and Type I IFN stimulated cells. LyzMcre mediated knockdown of KLF4 in BMMs resulted in a decreased secretion of proinflammatory cytokines and enhanced IL-10 release. In summary, we showed that pneumococci-related KLF4 induction in macrophages is mediated via a PAMP-DAMP induction mechanism involving a hitherto unknown host cell DNA sensor leading to a more proinflammatory macrophage phenotype.

Highlights Activation of invariant natural killer T cells eliminated senescent cells in vivoRemoval of senescent preadipocytes improves glucose control in obese mice Removal of senescent cells decreased lung fibrosis and improved survival Human iNKT cells were preferentially cytotoxic to senescent lung fibroblasts Arora et al., Med 2,[1][2][3][4][5][6][7][8][9][10][11][12][13]

Context The effect of 6-gingerol (6G), the bioactive component of Zingiber officinale Roscoe (Zingiberaceae), in the reduction of Vibrio cholerae (Vibrionaceae)-induced inflammation has not yet been reported. Objective This study reports the anti-inflammatory effect of 6-gingerol against V. cholerae-induced inflammation in intestinal epithelial (Int 407) cells. Materials and methods Cell viability assay was performed to determine the working concentration of 6G. Elisa and RT-PCR were performed with Int 407 cells treated with 50 mM 6G and 100 multiplicity of infection (MOI) V. cholerae for 0, 2, 3, 3.5, 6 and 8 h to determine the concentration of IL-8, IL-6, IL-1a and IL-1b in both protein and RNA levels. Furthermore, the effect of 50 mM 6G on upstream MAP-kinases and NF-jB signalling pathways was evaluated at 0, 10, 15, 30, 60 and 90 min. Results The effective dose (ED 50 ) value of 6G was found to be 50 mM as determined by cell viability assay. Pre-treatment with 50 mM 6G reduced V. cholerae infection-triggered levels of IL-8, IL-6, IL-1a and IL-1b by 3.2-fold in the protein level and two-fold in the RNA level at 3.5 h. The levels of MAPkinases signalling molecules like p38 and ERK1/2 were also reduced by two-and three-fold, respectively, after 30 min of treatment. Additionally, there was an increase in phosphorylated IkBa and down-regulation of p65 resulting in down-regulation of NF-jB pathway. Conclusion Our results showed that 6G could modulate the anti-inflammatory responses triggered by V. cholerae-induced infection in intestinal epithelial cells by modulating NF-jB pathway.ARTICLE HISTORY

In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10 6 CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates.