A single-cycle herpes simplex virus (HSV) deleted in glycoprotein D (ΔgD-2) elicited high titer HSV-specific antibodies (Abs) that (i) were rapidly transported into the vaginal mucosa; (ii) elicited antibody-dependent cell-mediated cytotoxicity but little neutralization; (iii) provided complete protection against lethal intravaginal challenge; and (iv) prevented establishment of latency in mice. However, clinical isolates may differ antigenically and impact vaccine efficacy. To determine the breadth and further define mechanisms of protection of this vaccine candidate, we tested ΔgD-2 against a panel of clinical isolates in a murine skin challenge model. The isolates were genetically diverse, as evidenced by genomic sequencing and in vivo virulence. Prime and boost immunization (s.c.) with live but not heat- or UV-inactivated ΔgD-2 completely protected mice from challenge with the most virulent HSV-1 and HSV-2 isolates. Furthermore, mice were completely protected against 100 times the lethal dose that typically kills 90% of animals (LD90) of a South African isolate (SD90), and no latent virus was detected in dorsal root ganglia. Immunization was associated with rapid recruitment of HSV-specific FcγRIII- and FcγRIV-activating IgG2 Abs into the skin, resolution of local cytokine and cellular inflammatory responses, and viral clearance by day 5 after challenge. Rapid clearance and the absence of latent virus suggest that ΔgD-2 elicits sterilizing immunity.
Christopher D. Petro, Brian Weinrick, Nazanin Khajoueinejad, Clare Burn, Rani Sellers, William R. Jacobs Jr, Betsy C. Herold
It is well established that maladaptive innate immune responses to sterile tissue injury represent a fundamental mechanism of disease pathogenesis. In the context of cardiac ischemia reperfusion injury, neutrophils enter inflamed heart tissue, where they play an important role in potentiating tissue damage and contributing to contractile dysfunction. The precise mechanisms that govern how neutrophils are recruited to and enter the injured heart are incompletely understood. Using a model of cardiac transplant–mediated ischemia reperfusion injury and intravital 2-photon imaging of beating mouse hearts, we determined that tissue-resident CCR2+ monocyte–derived macrophages are essential mediators of neutrophil recruitment into ischemic myocardial tissue. Our studies revealed that neutrophil extravasation is mediated by a TLR9/MyD88/CXCL5 pathway. Intravital 2-photon imaging demonstrated that CXCL2 and CXCL5 play critical and nonredundant roles in guiding neutrophil adhesion and crawling, respectively. Together, these findings uncover a specific role for a tissue-resident monocyte-derived macrophage subset in sterile tissue inflammation and support the evolving concept that macrophage ontogeny is an important determinant of function. Furthermore, our results provide the framework for targeting of cell-specific signaling pathways in myocardial ischemia reperfusion injury.
Wenjun Li, Hsi-Min Hsiao, Ryuji Higashikubo, Brian T. Saunders, Ankit Bharat, Daniel R. Goldstein, Alexander S. Krupnick, Andrew E. Gelman, Kory J. Lavine, Daniel Kreisel
Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor+ (p75NTR+) fibroblasts and homeostatic chemokine–producing fibroblasts inside TLTs, and retinoic acid–producing fibroblasts around TLTs. Deletion of CD4+ cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.
Yuki Sato, Akiko Mii, Yoko Hamazaki, Harumi Fujita, Hirosuke Nakata, Kyoko Masuda, Shingo Nishiyama, Shinsuke Shibuya, Hironori Haga, Osamu Ogawa, Akira Shimizu, Shuh Narumiya, Tsuneyasu Kaisho, Makoto Arita, Masashi Yanagisawa, Masayuki Miyasaka, Kumar Sharma, Nagahiro Minato, Hiroshi Kawamoto, Motoko Yanagita
Over one-fifth of North American women of childbearing age are obese, putting these women at risk for a variety of detrimental chronic diseases. In addition, obesity increases the risk for developing major complications during pregnancy. The mechanisms by which obesity contributes to pregnancy complications and loss remain unknown. Increasing evidence indicates that obesity results in major changes to adipose tissue immune cell composition and function; whether or not obesity also affects immune function in the uterus has not been explored. Here we investigated the effect of obesity on uterine natural killer (uNK) cells, which are essential for uterine artery remodeling and placental development. Using a cohort of obese or lean women, we found that obesity led to a significant reduction in uNK cell numbers accompanied with impaired uterine artery remodeling. uNK cells isolated from obese women had altered expression of genes and pathways associated with extracellular matrix remodeling and growth factor signaling. Specifically, uNK cells were hyper-responsive to PDGF, resulting in overexpression of decorin. Functionally, decorin strongly inhibited placental development by limiting trophoblast survival. Together, these findings establish a potentially new link between obesity and poor pregnancy outcomes, and indicate that obesity-driven changes to uterine-resident immune cells critically impair placental development.
Sofie Perdu, Barbara Castellana, Yoona Kim, Kathy Chan, Lauren DeLuca, Alexander G. Beristain
The deubiquitinase-encoding gene
Yingai Jane Jin, Sally Wang, Joshua Cho, M. Angelica Selim, Tim Wright, George Mosialos, Jennifer Y. Zhang
Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (
Elizabeth R. Davies, Joanne F.C. Kelly, Peter H. Howarth, David I. Wilson, Stephen T. Holgate, Donna E. Davies, Jeffrey A. Whitsett, Hans Michael Haitchi
Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to
Kong Chen, Brian T. Campfield, Sally E. Wenzel, Jeremy P. McAleer, James L. Kreindler, Geoffrey Kurland, Radha Gopal, Ting Wang, Wei Chen, Taylor Eddens, Kathleen M. Quinn, Mike M. Myerburg, William T. Horne, Jose M. Lora, Brian K. Albrecht, Joseph M. Pilewski, Jay K. Kolls
Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl– cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI.
Orhan Efe, Janet D. Klein, Lauren M. LaRocque, Huiwen Ren, Jeff M. Sands
Within the CNS, a dysregulated hemostatic response contributes to both hemorrhagic and ischemic strokes. Tissue factor (TF), the primary initiator of the extrinsic coagulation cascade, plays an essential role in hemostasis and also contributes to thrombosis. Using both genetic and pharmacologic approaches, we characterized the contribution of neuroectodermal (NE) cell TF to the pathophysiology of stroke. We used mice with various levels of TF expression and found that astrocyte TF activity reduced to ~5% of WT levels was still sufficient to maintain hemostasis after hemorrhagic stroke but was also low enough to attenuate inflammation, reduce damage to the blood-brain barrier, and improve outcomes following ischemic stroke. Pharmacologic inhibition of TF during the reperfusion phase of ischemic stroke attenuated neuronal damage, improved behavioral deficit, and prevented mortality of mice. Our data demonstrate that NE cell TF limits bleeding complications associated with the transition from ischemic to hemorrhagic stroke and also contributes to the reperfusion injury after ischemic stroke. The high level of TF expression in the CNS is likely the result of selective pressure to limit intracerebral hemorrhage (ICH) after traumatic brain injury but, in the modern era, poses the additional risk of increased ischemia-reperfusion injury after ischemic stroke.
Shaobin Wang, Brandi Reeves, Erica M. Sparkenbaugh, Janice Russell, Zbigniew Soltys, Hua Zhang, James E. Faber, Nigel S. Key, Daniel Kirchhofer, D. Neil Granger, Nigel Mackman, Rafal Pawlinski
Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin αvβ6 signaling, as judged by its ability to inhibit these pathways in cnr1–/– but not in nos2–/– mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.
Resat Cinar, Malliga R. Iyer, Ziyi Liu, Zongxian Cao, Tony Jourdan, Katalin Erdelyi, Grzegorz Godlewski, Gergő Szanda, Jie Liu, Joshua K. Park, Bani Mukhopadhyay, Avi Z. Rosenberg, Jeih-San Lieow, Robin G. Lorenz, Pal Pacher, Robert B. Innis, George Kunos
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