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1. The Enhancer-Binding Protein MifR, an Essential Regulator of α-Ketoglutarate Transport, Is Required for Full Virulence of Pseudomonas aeruginosa PAO1 in a Mouse Model of Pneumonia

   https://doi.org/10.1128/iai.00136-22  

   Xiong, Weichuan ; Perna, Alexander ; Jacob, Ikechukwu B. ; Lundgren, Benjamin R. ; Wang, Guirong ( October 2022 , Infection and Immunity)

   Brodsky, Igor E. (Ed.)

   ABSTRACT The opportunistic human pathogen Pseudomonas aeruginosa PAO1 has an extensive metabolism, enabling it to utilize a wide range of structurally diverse compounds to meet its nutritional and energy needs. Interestingly, the utilization of some of the more unusual compounds often associated with a eukaryotic-host environment is regulated via enhancer-binding proteins (EBPs) in P. aeruginosa . Whether the utilization of such compounds and the EBPs involved contribute to the pathogenesis of P. aeruginosa remains to be fully understood. To narrow this gap, we investigated the roles of the EBPs EatR (regulator of ethanolamine catabolism), DdaR (regulator of methylarginine catabolism), and MifR (regulator of α-ketoglutarate or α-KG transport) in the virulence of P. aeruginosa PAO1 in a pneumonia-induced septic mouse model. Deletion of genes encoding EatR and DdaR had no significant effect on the mortality of P. aeruginosa PAO1-infected mice compared to wide-type (WT) PAO1-infected mice. In contrast, infected mice with Δ mifR mutant exhibited a significant reduction (~50%) in the mortality rate compared with WT PAO1 ( P < 0.05). Infected mice with Δ mifR PAO1 had lower lung injury scores, fewer inflammatory cells, decreased proinflammatory cytokines, and decreased apoptosis and cell death compared to mice infected with WT PAO1more »( P < 0.05). Furthermore, molecular analysis revealed decreased NLRP3 inflammasome activation in infected mice with Δ mifR PAO1 compared to WT PAO1 ( P < 0.05). These results suggested that the utilization of α-KG was a contributing factor in P. aeruginosa -mediated pneumonia and sepsis and that MifR-associated regulation may be a potential therapeutic target for P. aeruginosa infectious disease.« less
2. Surfactant proteins and innate immunity of otitis media

   https://doi.org/10.1177/17534259221123309  

   Abdel-Razek, Osama ; Audlin, Jason ; Poe, Dennis S. ; Wang, Guirong ( October 2022 , Innate Immunity)

   Otitis media (OM) is the most common disease among young children and one of the most frequent reasons to visit the pediatrician. Development of OM requires nasopharyngeal colonization by a pathogen which must gain access to the tympanic cavity through the eustachian tube (ET) along with being able to overcome the defense mechanisms of the immune system and middle ear mucosa. OM can be caused by viral or bacterial infection. The three main bacterial pathogens are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Innate immunity is important in OM resolution as the disease occurs in very young children before the development of specific immunity. Elements of innate immunity include natural barriers and pattern recognition receptors such as Toll like receptors (TLRs), and Nod like receptors (NLRs). Surfactant proteins A (SP-A) and D (SP-D) act as pattern recognition receptors and are found in the lung and many other tissues including the ET and the middle ear where they probably function in host defense. Surfactant has a potential for use in the treatment of OM due to surface tension lowering function in the ET, and the possible immune functions of SP-D and SP-A in the middle ear and ET.
3. Circadian clock protein Rev-erbα regulates neuroinflammation

   https://doi.org/10.1073/pnas.1812405116  

   Griffin, Percy ; Dimitry, Julie M. ; Sheehan, Patrick W. ; Lananna, Brian V. ; Guo, Chun ; Robinette, Michelle L. ; Hayes, Matthew E. ; Cedeño, Michelle R. ; Nadarajah, Collin J. ; Ezerskiy, Lubov A. ; et al ( February 2019 , Proceedings of the National Academy of Sciences)

   Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα^−/−mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα^−/−mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα^−/−microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα^−/−mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial culturesmore »exacerbated oxidative damage in cultured neurons. Rev-erbα^−/−mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

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4. Mesenchymal stromal cells expressing a dominant-negative high mobility group A1 transgene exhibit improved function during sepsis

   https://doi.org/10.1002/JLB.4A0720-424R  

   Kwon, Min-Young ; Ghanta, Sailaja ; Ng, Julie ; Castano, Ana P. ; Han, Junwen ; Ith, Bonna ; Lederer, James A. ; El-Chemaly, Souheil ; Chung, Su Wol ; Liu, Xiaoli ; et al ( January 2021 , Journal of Leukocyte Biology)

   High mobility group (HMG)A proteins are nonhistone chromatin proteins that bind to the minor groove of DNA, interact with transcriptional machinery, and facilitate DNA-directed nuclear processes. HMGA1 has been shown to regulate genes involved with systemic inflammatory processes. We hypothesized that HMGA1 is important in the function of mesenchymal stromal cells (MSCs), which are known to modulate inflammatory responses due to sepsis. To study this process, we harvested MSCs from transgenic (Tg) mice expressing a dominant-negative (dn) form of HMGA1 in mesenchymal cells. MSCs harvested from Tg mice contained the dnHMGA1 transgene, and transgene expression did not change endogenous HMGA1 levels. Immunophenotyping of the cells, along with trilineage differentiation revealed no striking differences between Tg and wild-type (WT) MSCs. However, Tg MSCs growth was decreased compared with WT MSCs, although Tg MSCs were more resistant to oxidative stress-induced death and expressed less IL-6. Tg MSCs administered after the onset of Escherichia coli-induced sepsis maintained their ability to improve survival when given in a single dose, in contrast with WT MSCs. This survival benefit of Tg MSCs was associated with less tissue cell death, and also a reduction in tissue neutrophil infiltration and expression of neutrophil chemokines. Finally, Tg MSCsmore »promoted bacterial clearance and enhanced neutrophil phagocytosis, in part through their increased expression of stromal cell-derived factor-1 compared with WT MSCs. Taken together, these data demonstrate that expression of dnHMGA1 in MSCs provides a functional advantage of the cells when administered during bacterial sepsis.

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5. Chrysin alleviates imiquimod-induced psoriasis-like skin inflammation and reduces the release of CCL20 and antimicrobial peptides

   https://doi.org/10.1038/s41598-020-60050-1  

   Li, Hsin-Ju ; Wu, Nan-Lin ; Pu, Chi-Ming ; Hsiao, Chien-Yu ; Chang, Der-Chen ; Hung, Chi-Feng ( February 2020 , Scientific Reports)

   Psoriasis is a common non-contagious chronic inflammatory skin lesion, with frequent recurrence. It mainly occurs due to aberrant regulation of the immune system leading to abnormal proliferation of skin cells. However, the pathogenic mechanisms of psoriasis are not fully understood. Although most of the current therapies are mostly efficient, the side effects can result in therapy stop, which makes the effectiveness of treatment strategies limited. Therefore, it is urgent and necessary to develop novel therapeutics. Here, we investigated the efficacy of chrysin, a plant flavonoid, which we previously reported to possess strong antioxidant and anti-inflammatory effects, against psoriasis-like inflammation. Our results revealed that chrysin significantly attenuated imiquimod-induced psoriasis-like skin lesions in mice, and improved imiquimod-induced disruption of skin barrier. Moreover, the TNF-α, IL-17A, and IL-22-induced phosphorylation of MAPK and JAK-STAT pathways, and activation of the NF-κB pathway were also attenuated by chrysin pretreatment of epidermal keratinocytes. Most importantly, chrysin reduced TNF-α-, IL-17A-, and IL-22-induced CCL20 and antimicrobial peptide release from epidermal keratinocytes. Thus, our findings indicate that chrysin may have therapeutic potential against inflammatory skin diseases. Our study provides a basis for further investigating chrysin as a novel pharmacologic agent and contributes to the academic advancement in the fieldmore »of Chinese herbal medicine.

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