Circulating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type-A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and GFP bone marrow (BM) chimeric approach, we find neuroprotection and lack of significant motor deficits that is marked by reduced monocyte/macrophage cortical infiltration, and increased number of arginase-1-postivity in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to anti-inflammatory that includes increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocyte/macrophages. In Epha4 BM-deficient mice, cortical-isolated GFP+ monocyte/macrophages displayed a phenotypic shift from classical to an intermediate subtype, which displayed reduced Ly6chi concomitant with increased Ly6clo- and Tie2-expressing populations. Furthermore, clodronate liposome-mediated monocyte depletion mimicked these effects in wild-type but resulted in attenuation of phenotype in Epha4 BM-deficient mice suggesting control over monocyte polarization not recruitment dictates tissue damage. Thus, coordination of monocyte pro-inflammatory polarization by Epha4 is a key regulatory step mediating neural tissue damage.
Elizabeth A. Kowalski, Eman Soliman, Colin Kelly, Erwin Kristobal Gudenschwager Basso, John Leonard, Kevin J. Pridham, Jing Ju, Alison M. Cash, Amanda Hazy, Caroline de Jager, Alexandra M. Kaloss, Hanzhang Ding, Raymundo D. Hernandez, Gabriel M. Coleman, Xia Wang, Michelle L. Olsen, Alicia M. Pickrell, Michelle H. Theus
Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, to increase morbidity and mortality. Nanoparticles are a potential practical therapeutic that could reduce exaggerated innate immune responses within the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via intravenous injection to aged mice at day 3 post-infection when the hyperinflammatory innate immune response is already established. During infection, we found that ONP-302 treatment reduced the numbers of inflammatory monocytes within the lungs and increased their number in both the liver and spleen, without impacting viral clearance. Importantly, cargo-free nanoparticles reduced lung damage, histological lung inflammation and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. In conclusion, ONP-302 improves outcomes in influenza-infected aged mice. Thus, our study provides fundamental information concerning a practical therapeutic which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections.
William J. Kelley, Kathleen M. Wragg, Judy Chen, Tushar Murthy, Qichen Xu, Michael T. Boyne II, Joseph R. Podojil, Adam Elhofy, Daniel R. Goldstein
Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a pro-mnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.
Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, Pierre-Marie Lledo
Serum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. Though sNFL correlates with cerebrospinal fluid (CSF) NFL (cNFL), 40-60% of variance remains unexplained. We aimed to mathematically adjust sNFL to strengthen its clinical value. We measured NFL in blinded fashion in 1,138 matched CSF and serum samples from 571 subjects. Multiple linear regression (MLR) models constructed in the training cohort were validated in an independent cohort. MLR model that included age, blood urea nitrogen (BUN), alkaline phosphatase (AP), creatinine, and weight improved correlations of cNFL with sNFL (from R2 = 0.57 to 0.67). Covariate-adjustment significantly improved the correlation of sNFL with number of contrast-enhancing lesions (from R2 = 0.18 to 0.28; 36% improvement) in the validation cohort. Unexpectedly, only sNFL, but not cNFL, weakly but significantly correlated with cross-sectional MS severity outcomes. Investigating two non-overlapping hypotheses, we show that subjects with proportionally higher sNFL to cNFL have higher clinical and radiological evidence of spinal cord (SC) injury, and likely release NFL from peripheral axons into blood, bypassing the CSF. Thus, sNFL captures two sources of axonal injury: central and peripheral; the latter reflecting SC damage, which primarily drives disability progression in MS.
Peter Kosa, Ruturaj Masvekar, Mika Komori, Jonathan Phillips, Vighnesh Ramesh, Mihael Varosanec, Mary Sandford, Bibiana Bielekova
The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumours. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidaemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, impaired mTORC1 signalling in fat (decreased) and liver (increased) co-segregated with defective epithelial-mesenchymal transition, being prominent the decreased expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
Aina Lluch, Sonia R. Veiga, Jèssica Latorre, José M. Moreno-Navarrete, Núria Bonifaci, Van Dien Nguyen, You Zhou, Marcus Horing, Gerhard Liebisch, Vesa M. Olkkonen, David Llobet-Navas, George Thomas, Ruth Rodriguez-Barrueco, José M. Fernández-Real, Sara C. Kozma, Francisco J. Ortega
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