Alveolar macrophages (AM) play a central role in initiation and resolution of lung inflammation, but the integration of these opposing core functions is poorly understood. AM expression of cholesterol-25-hydroxylase (CH25H), the primary biosynthetic enzyme for 25-hydroxycholesterol (25HC), far exceeds that of macrophages in other tissues, but no role for CH25H has been defined in lung biology. As 25HC is an agonist for the anti-inflammatory nuclear receptor, Liver X Receptor (LXR), we speculated that CH25H might regulate inflammatory homeostasis in the lung. Here, we show that, of natural (oxy)sterols, 25HC is uniquely induced in the inflamed lung of mice and humans. Ch25h-/- mice fail to induce 25HC and LXR target genes in the lung after LPS inhalation and exhibit delayed resolution of airway neutrophilia which can be rescued by systemic treatment with either 25HC or synthetic LXR agonists. LXR-null mice also display delayed resolution, suggesting that native oxysterols promote resolution. During resolution, Ch25h is induced in macrophages upon their encounter with apoptotic cells and is required for LXR-dependent prevention of AM lipid overload, induction of Mertk, efferocytic resolution of airway neutrophilia, and induction of TGFb. CH25H/25HC/LXR is thus an inducible metabolic axis that programs AMs for efferocytic resolution of inflammation.
Jennifer H. Madenspacher, Eric D. Morrell, Kymberly M. Gowdy, Jeffrey G. McDonald, Bonne M. Thompson, Ginger W. Muse, Jennifer Martinez, Seddon Y. Thomas, Carmen Mikacenic, Jerry A. Nick, Edward Abraham, Stavros Garantziotis, Renee D. Stapleton, Julie M. Meacham, Mary Jane Thomassen, William J. Janssen, Donald N. Cook, Mark M. Wurfel, Michael B. Fessler
In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have potential to propagate inflammation and microvascular thrombosis — including in the lungs of patients with acute respiratory distress syndrome. While elevated levels of blood neutrophils predict worse outcomes in COVID-19, the role of NETs has not been investigated. We now report that sera from patients with COVID-19 (n = 50 patients, n = 84 samples) have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute phase reactants including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. In summary, these data reveal high levels of NETs in many patients with COVID-19, where they may contribute to cytokine release and respiratory failure. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts, and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.
Yu Zuo, Srilakshmi Yalavarthi, Hui Shi, Kelsey Gockman, Melanie Zuo, Jacqueline A. Madison, Christopher N. Blair, Andrew Weber, Betsy J. Barnes, Mikala Egeblad, Robert J. Woods, Yogendra Kanthi, Jason S. Knight
The role CD4+ T-cells play in tumor immunity is less well-appreciated than the cytotoxic role of CD8+ T-cells. Despite clear evidence for CD4+ T-cell dependency across multiple immunotherapies, the mechanisms by which CD4+ T-cells infiltrate tumors remain poorly understood. Prior studies by our group have shown in a mouse model of pancreatic cancer that systemic activation of the cell-surface TNF superfamily member CD40 drives T-cell infiltration into tumors and in combination with immune checkpoint blockade, leads to durable tumor regressions and cures that depend on both CD8+ and CD4+ T-cells. Here, we used single-cell transcriptomics to examine the tumor microenvironment following treatment with agonist CD40 antibody with or without immune checkpoint blockade. We show that intratumoral myeloid cells produce the chemokine CCL5 in response to CD40 agonist and that CCL5 mediates an influx of CD4+ T-cells into the tumor microenvironment. Disruption of CCL5 genetically or pharmacologically mitigates the influx of CD4+ but not CD8+ T-cells into tumors and blunts the therapeutic efficacy of immunotherapy. These findings highlight a previously unappreciated role for CCL5 in selectively mediating CD4+ T-cell tumor infiltration in response to effective immunotherapy.
Austin P. Huffman, Jeffrey H. Lin, Samuel I. Kim, Katelyn T. Byrne, Robert H. Vonderheide
Background: The Coronavirus Disease-2019 (COVID-19), infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a severe outbreak in China. The host immunity of COVID-19 patients is unknown. Methods: The routine laboratory tests and host immunity in COVID-19 patients with different severity of illness were compared after patient admission. Results: A total of 65 SARS-CoV-2-positive patients were classified as mild (n=30), severe (n=20), and extremely severe (n=15) illness. Many routine laboratory tests such as ferritin, lactate dehydrogenase and D-dimer were increased in severe and extremely severe patients. The absolute numbers of CD4+ T cells, CD8+ T cells and B cells were all gradually decreased with increased severity of illness. The activation markers such as HLA-DR and CD45RO expressed on CD4+ and CD8+ T cells were increased in severe and extremely severe patients compared with mild patients. The co-stimulatory molecule CD28 had opposite results. The percentage of natural regulatory T cells was decreased in extremely severe patients. The percentage of IFN-γ producing CD8+ T cells was increased in both severe and extremely severe patients compared with mild patients. The percentage of IFN-γ producing CD4+ T cells was increased in extremely severe patients. The IL-2R, IL-6, and IL-10 were all increased in extremely severe patients. The activation of DC and B cells was decreased in extremely severe patients. Conclusions: The number and function of T cells are inconsistent in COVID-19 patients. The hyperfunction of CD4+ and CD8+ T cells is associated with the pathogenesis of extremely severe SARS-CoV-2 infection.
Feng Wang, Hongyan Hou, Ying Luo, Guoxing Tang, Shiji Wu, Min Huang, Weiyong Liu, Yaowu Zhu, Qun Lin, Liyan Mao, Minghao Fang, Huilan Zhang, Ziyong Sun
Discovery strategies commonly focus on the identification of chemical libraries or natural products, but the modulation of endogenous ligands offers a much better therapeutic strategy due to their low adverse potential. Recently, we have seen that hexadecanamide (Hex) is present in hippocampal nuclei of normal mice as an endogenous ligand of peroxisome proliferator-activated receptor alpha (PPARα). This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (BDNF) from hippocampal neurons via PPARα. The level of Hex was less in the hippocampus of 5xFAD mice as compared to non-Tg mice. Oral administration of Hex increased the level of this molecule in the hippocampus to stimulate BDNF and its downstream plasticity-associated molecules, promote synaptic functions in the hippocampus and improve memory and learning in 5xFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5xFADPparα-null (5x with global PPARα-/-) and 5xFADPparα-ΔHippo (5x with hippocampus-specific PPARα-/-) mice, indicating an essential role of hippocampal PPARα in Hex-mediated improvement in hippocampal functions. This is the first demonstration of protection of hippocampal functions by oral administration of a hippocampus-based drug, suggesting that hexadecanamide may be explored for therapeutic intervention in AD.
Dhruv R. Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank Gonzalez, Kalipada Pahan
Bone fractures are a major cause of morbidity and mortality, particularly in diabetic patients, who have a high incidence of fractures and exhibit poor fracture healing. Coordinated expression of osteoblast-derived vascular endothelial growth factor (VEGF) and bone morphogenic proteins (BMPs) is essential for fracture repair. The NO/cGMP/protein kinase G (PKG) signaling pathway mediates osteoblast responses to estrogens and mechanical stimulation, but the pathway’s role in bone regeneration is unknown. Here, we used a mouse cortical defect model to simulate bone fractures and studied osteoblast-specific PKG1 knockout and diabetic mice. The knock-out mice had normal bone micro-architecture, but after injury exhibited poor bone regeneration, with decreased osteoblasts, collagen deposition, and microvessels in the bone defect area. Primary osteoblasts and tibiae from the knock-out mice expressed low amounts of Vegfa and Bmp2/4 mRNAs, and PKG1 was required for cGMP-stimulated expression of these genes. Diabetic mice also demonstrated low Vegfa and Bmp2/4 expression in bone and impaired bone regeneration after injury; notably, the cGMP-elevating agent cinaciguat restored Vegfa and BMP2/4 expression, and full bone healing. We conclude that PKG1 is a key orchestrator of VEGF and BMP signaling during bone regeneration and propose pharmacological PKG activation as a novel therapeutic approach to enhance fracture healing.
Nadine Schall, Julian J. Garcia, Hema Kalyanaraman, Shyamsundar Pal China, Jenna J. Lee, Robert L. Sah, Alexander Pfeifer, Renate B. Pilz
Although aging represents the most important epidemiologic risk factor for fibrotic disease, the reasons for this are incompletely understood. Excess collagen deposition in tissues is the sine qua non of tissue fibrosis and can be viewed as an imbalance between collagen production and collagen degradation. Yet we still lack a detailed understanding of the changes that take place during development, maturation and aging in extracellular-matrix (ECM) dynamics. Resolution of fibrosis is impaired in aging and this impairment may explain why age is the most important risk factor for fibrotic diseases such as Idiopathic Pulmonary Fibrosis. However, ECM dynamics and impaired resolution of fibrosis in aging remain understudied. Here we show that cell-mediated collagen uptake and degradation are diminished in aged animals and this finding correlates with downregulation of the collagen endocytic receptor Mrc2. We identify Myeloid Zinc Finger-1 as a novel transcriptional regulator of Mrc2 and both this transcription factor and Mrc2 are downregulated in multiple tissues and organisms in an age-dependent manner. Thus, cell-mediated degradation of collagen is an essential process that promotes resolution of fibrosis and impairment in this process contributes to age-related fibrosis.
Michael J. Podolsky, Christopher D. Yang, Carlos Lizama, Ritwik Datta, Steven K. Huang, Stephen L. Nishimura, Sarah L. Dallas, Paul Wolters, Claude Jourdan Le Saux, Kamran Atabai
Muscle progenitor cell fusion is required for the formation and regeneration of multinucleated skeletal muscle fibers. Chronic muscle regeneration in Duchenne muscular dystrophy (DMD) is characterized by ongoing fusion of satellite cell (SC) progeny, but the effects of fusion on disease and the mechanisms by which fusion is accomplished in this setting are not fully understood. Using the mdx mouse model of DMD, we deleted the fusogenic protein Myomaker in SCs or myofibers. Following deletion in SCs, mice displayed a complete lack of myocyte fusion, resulting in severe muscle loss, enhanced fibrosis, and significant functional decline. Reduction of Myomaker in mature myofibers in mdx mice, however, led to minimal alterations in fusion dynamics. Unexpectedly, myofiber-specific deletion of myomaker resulted in improvement of disease phenotype, with enhanced function and decreased muscle damage. Our data indicate that Myomaker has divergent effects on dystrophic disease severity depending upon its compartment of expression. These findings show that myocyte fusion is absolutely required for effective regeneration in DMD, but persistent Myomaker expression in myofibers due to ongoing fusion may have unintended deleterious consequences for muscle integrity. Thus, sustained activation of a component of the myogenic program in dystrophic myofibers exacerbates disease.
Michael J. Petrany, Taejeong Song, Sakthivel Sadayappan, Douglas P. Millay
Complications of COVID-19 have been particularly severe among older adults, who are the focus of this article. Public policy goals should prioritize pandemic preparedness in nursing homes, as well as civic and local government-based support programs for community-dwelling older adults, to ensure that risk of infection is mitigated while promoting wellness during a period of stress and uncertainty.
John P. Mills, Keith S. Kaye, Lona Mody
Inflammation is a major risk factor of morbidity and mortality in older adults. Although its precise etiology is unknown, low-grade inflammation in older adults is commonly associated with increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota. The increasing older population and lack of treatments to reduce aging-related microbiota dysbiosis, leaky gut and inflammation culminates on a rise in aging-related comorbidities, constituting a significant public health concern. Here we demonstrate that a human-origin probiotic cocktail containing 5-Lactobacillus and 5 Enterococcus strains isolated from healthy infant’s gut prevents high-fat diet (HFD)-induced microbiota dysbiosis, leaky gut, inflammation, metabolic dysfunctions and physical function decline in older mice. Probiotic-modulated gut microbiota primarily reduced leaky gut by increasing tight junctions, which in turn reduced inflammation. Mechanistically, probiotics modulated microbiota in a way to increases bile salt hydrolase activity, which in turn increased taurine abundance in the gut that stimulated tight junctions and suppressed gut leakiness. Further, in Caenorhabditis elegans, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function. The results suggest that such probiotic therapies could prevent or treat aging-related leaky gut and inflammation in elderly.
Shokouh Ahmadi, Shaohua Wang, Ravinder Nagpal, Bo Wang, Shalini Jain, Atefeh Razazan, Sidharth P. Mishra, Xuewei Zhu, Zhan Wang, Kylie Kavanagh, Hariom Yadav
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