scholarly journals Enhanced inflammation in aged mice following infection with Streptococcus pneumoniae is associated with decreased IL-10 and augmented chemokine production

2015 ◽  
Vol 308 (6) ◽  
pp. L539-L549 ◽  
Author(s):  
Andrew E. Williams ◽  
Ricardo J. José ◽  
Jeremy S. Brown ◽  
Rachel C. Chambers
Keyword(s):  
Streptococcus Pneumoniae ◽  
Young Adult ◽  
Inflammatory Responses ◽  
Severe Pneumonia ◽  
Chemokine Production ◽  
Aged Mice ◽  
Adult Mice ◽  
The Impact ◽  
Bacterial Outgrowth ◽  
Young Mice

Streptococcus pneumoniae is the most common cause of severe pneumonia in the elderly. However, the impact of aging on the innate inflammatory response to pneumococci is poorly defined. We compared the innate immune response in old vs. young adult mice following infection with S. pneumoniae. The accumulation of neutrophils recovered from bronchoalveolar lavage fluid and lung homogenates was increased in aged compared with young adult mice, although bacterial outgrowth was similar in both age groups, as were markers of microvascular leak. Aged mice had similar levels of IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor following S. pneumoniae infection, compared with young mice, but increased levels of the chemokines CXCL9, CXCL12, CCL3, CCL4, CCL5, CCL11, and CCL17. Moreover, levels of IL-10 were significantly lower in aged animals. Neutralization of IL-10 in infected young mice was associated with increased neutrophil recruitment but no decrease in bacterial outgrowth. Furthermore, IL-10 neutralization resulted in increased levels of CCL3, CCL5, and CXCL10. We conclude that aging is associated with enhanced inflammatory responses following S. pneumoniae infection as a result of a compromised immunomodulatory cytokine response.

Abstract TP78: Combination of Neuroprotective Drug and Neural Stem Cells Benefits Aged Stroke Mice with Delayed Tissue Plasminogen Activator Treatment

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Auston Eckert ◽  
Milton H Hamblin ◽  
Jean-Pyo Lee
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Inflammatory Drug ◽  
Aged Mice ◽  
Post Stroke ◽  
Adult Mice ◽  
Tissue Plasminogen

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

Coagulation factor XI improves host defence during murine pneumonia-derived sepsis independent of factor XII activation

2017 ◽  
Vol 117 (08) ◽  
pp. 1601-1614 ◽  
Author(s):  
Ingrid Stroo ◽  
Sacha Zeerleder ◽  
Chao Ding ◽  
Brenda Luken ◽  
Joris Roelofs ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Klebsiella Pneumoniae ◽  
Inflammatory Responses ◽  
Coagulation Factor ◽  
Host Defence ◽  
Human Neutrophils ◽  
Factor Xii ◽  
Factor Xi ◽  
Phagocytic Capacity ◽  
Bacterial Outgrowth

SummaryBacterial pneumonia, the most common cause of sepsis, is associated with activation of coagulation. Factor XI (FXI), the key component of the intrinsic pathway, can be activated via factor XII (FXII), part of the contact system, or via thrombin. To determine whether intrinsic coagulation is involved in host defence during pneumonia and whether this is dependent on FXII activation, we infected in parallel wild-type (WT), FXI knockout (KO) and FXII KO mice with two different clinically relevant pathogens, the Gram-positive bacterium Streptococcus pneumoniae and the Gram-negative bacterium Klebsiella pneumoniae, via the airways. FXI deficiency worsened survival and enhanced bacterial outgrowth in both pneumonia models. This was accompanied with enhanced inflammatory responses in FXI KO mice. FXII KO mice were comparable with WT mice in Streptococcus pneumoniae pneumonia. On the contrary, FXII deficiency improved survival and reduced bacterial outgrowth following infection with Klebsiella pneumoniae. In both pneumonia models, local coagulation was not impaired in either FXI KO or FXII KO mice. The capacity to phagocytose bacteria was impaired in FXI KO neutrophils and in human neutrophils where activation of FXI was inhibited. Deficiency for FXII or blocking activation of FXI via FXIIa had no effect on phagocytosis. Taken together, these data suggest that FXI protects against sepsis derived from Streptococcus pneumoniae or Klebsiella pneumoniae pneumonia at least in part by enhancing the phagocytic capacity of neutrophils by a mechanism that is independent of activation via FXIIa.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

2013 ◽  
Vol 210 (11) ◽  
pp. 2223-2237 ◽  
Author(s):  
Myriam N. Bouchlaka ◽  
Gail D. Sckisel ◽  
Mingyi Chen ◽  
Annie Mirsoian ◽  
Anthony E. Zamora ◽  
...  
Keyword(s):  
Critical Role ◽  
The Elderly ◽  
Mouse Tumor ◽  
Aged Mice ◽  
Liver Histopathology ◽  
Multiple Organs ◽  
The Impact ◽  
Young Mice

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.

scholarly journals Aging dampens the intestinal innate immune response during Clostridioides difficile infection and is associated with altered intestinal eosinophil mobilization

2020 ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Michael G. Dieterle ◽  
Kimberly C. Vendrov ◽  
Ingrid L. Bergin ◽  
Vincent B. Young
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Disease Severity ◽  
Advanced Age ◽  
Simultaneous Increase ◽  
Aged Mice ◽  
Age Related ◽  
Cellular Immune ◽  
The Impact ◽  
Young Mice

ABSTRACTClostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the impact of aging on the cellular immune response associated with C. difficile infection in the setting of advanced age remains to be well described. This study explores the effect of age on cellular immune responses in C. difficile infection as well as disease severity. Young adult mice (2-3 months old) and aged mice (22-28 months old) were rendered susceptible to C. difficile infection with cefoperazone and then infected with C. difficile strains of varying disease-causing potential. Aged mice infected with C. difficile develop more severe clinical disease, compared to young mice. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the cecum and colon of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice. Interestingly, while C. difficile infection in young mice was associated with a robust increase in cecal and colonic eosinophils, there was a complete lack of an intestinal eosinophil response in aged counterparts accompanied by a simultaneous increase in blood eosinophils with severe disease. These findings demonstrate that age-related alterations in immune responses are associated with significantly worse C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

scholarly journals Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging

2020 ◽  
Vol 117 (52) ◽  
pp. 33561-33569
Author(s):  
Megumi Inomata ◽  
Shuying Xu ◽  
Pallavi Chandra ◽  
Simin N. Meydani ◽  
Genzou Takemura ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Inflammatory Responses ◽  
The Elderly ◽  
Invasive Disease ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Murine Bone Marrow ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

scholarly journals Delayed Demyelination and Impaired Remyelination in Aged Mice in the Cuprizone Model

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 945 ◽  
Author(s):  
Stefan Gingele ◽  
Florian Henkel ◽  
Sandra Heckers ◽  
Thiemo M. Moellenkamp ◽  
Martin W. Hümmert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Animal Models ◽  
Corpus Callosum ◽  
Mature Adult ◽  
Aged Mice ◽  
Adult Mice ◽  
Regenerative Therapies ◽  
Young Mice

To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of MS patients. Furthermore, remyelination is very fast in young mice, hindering the examination of effects of remyelination-promoting agents. Thus, there is the need for a better animal model to study remyelination. We therefore aimed to establish the cuprizone model in aged mice. 6-month-old C57BL6 mice were fed with different concentrations of cuprizone (0.2–0.6%) for 5–6.5 weeks. De- and remyelination in the medial and lateral parts of the corpus callosum were analyzed by immunohistochemistry. Feeding aged mice 0.4% cuprizone for 6.5 weeks resulted in the best and most reliable administration scheme with virtually complete demyelination of the corpus callosum. This was accompanied by a strong accumulation of microglia and near absolute loss of mature oligodendrocytes. Subsequent remyelination was initially robust but remained incomplete. The remyelination process in mature adult mice better represents the age of MS patients and offers a better model for the examination of regenerative therapies.

Abstract 123: Age-Related Diminishment of the Subventricular Zone Cytogenic Response and Its Contributions to Motor Recovery After Cortical Infarcts

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Michael R Williamson ◽  
Stephanie Le ◽  
Ronald L Franzen ◽  
Michael R Drew ◽  
Theresa A Jones
Keyword(s):  
Young Adult ◽  
Subventricular Zone ◽  
Motor Recovery ◽  
Lineage Tracing ◽  
Stem Cell Markers ◽  
Middle Aged ◽  
Reaching Task ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related

Stroke increases proliferation within the subventricular zone (SVZ) cytogenic niche and causes subsequent migration of newborn cells towards the site of injury. We investigated the functional consequences of age-related blunting of the SVZ cytogenic response to ischemia. We found that there was a marked reduction in proliferation and neural stem cell markers within the SVZ of middle aged (aged 12-16 months) versus young adult (aged 3-5 months) mice in the intact brain and after photothrombotic infarcts in motor cortex. Using an inducible, heritable lineage tracing system (Nestin-CreER T2 :: Ai14 mice) to quantify SVZ-derived neural precursor cells (NPCs) that migrated towards the infarct, we found that there was a considerable age-related reduction in the number of NPCs in peri-infarct cortex. These findings indicate a marked diminishment of SVZ NPC proliferation and migration after focal ischemia by middle age. Next, we assessed the contributions of the SVZ cytogenic response to recovery of skilled motor function. We used glial fibrillary acidic protein-thymidine kinase mice to conditionally ablate NPCs with ganciclovir administration. In young adult mice, NPC ablation significantly impaired recovery of motor performance on the single seed reaching task after motor cortical infarcts. By contrast, NPC ablation did not affect motor recovery in middle aged mice. Importantly, the magnitude of recovery was less in middle aged mice—regardless of NPC ablation—than in control young adult mice. Middle aged mice recovered similarly to young adult mice lacking NPCs. These results indicate that SVZ cytogenesis contributes to functional improvements after cortical infarcts and that the diminishment of the cytogenic response with age may be implicated in age-related worsening of outcome after stroke. Restoration of SVZ cytogenesis in aged animals might improve behavioral recovery.

scholarly journals Roxithromycin Favorably Modifies the Initial Phase of Resistance against Infection with Macrolide-Resistant Streptococcus pneumoniae in a Murine Pneumonia Model

2007 ◽  
Vol 51 (5) ◽  
pp. 1741-1752 ◽  
Author(s):  
Yasuki Yasuda ◽  
Kei Kasahara ◽  
Fumiko Mizuno ◽  
Kazuyuki Nishi ◽  
Keiichi Mikasa ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Matrix Metalloproteinase ◽  
Virulence Factors ◽  
Inflammatory Responses ◽  
Western Blot Assay ◽  
Chemokine Production ◽  
Inflammatory Parameters ◽  
Matrix Metalloproteinase 7 ◽  
Inflammatory Processes

ABSTRACT Sub-MIC levels of macrolides down-regulate bacterial virulence factors and suppress inflammatory processes. The ability of macrolides to reduce the production of pneumolysin has been shown to explain the discrepancy between in vitro resistance and outcomes with macrolides against macrolide-resistant Streptococcus pneumoniae. In this study, we determined whether the ability of macrolides to regulate inflammatory processes is beneficial for innate resistance to macrolide-resistant pneumococci in a murine pneumonia model. Among the macrolides tested, only roxithromycin did not affect in vitro pneumococcal virulence factors at sub-MIC levels. Roxithromycin (1.25 to 10 mg/kg of body weight/day) was administered to mice by oral gavage for 3 days before infection with a resistant strain of S. pneumoniae. We evaluated the efficacy of the treatment by determining mouse survival curves and by measuring bacterial burdens and several inflammatory parameters in the airways. Pneumolysin and PspA in infected lungs were examined by Western blot assay. Roxithromycin at doses of ≥5 mg/kg/day increased the median survival time and retarded bacteremia without suppressing the production of pneumolysin and PspA in infected lungs. This treatment reduced matrix metalloproteinase-7 expression and activation and keratinocyte-derived chemokine production in the lungs, while it increased mononuclear cell responses in the lungs, with enhanced bacterial clearance. Concentrations of roxithromycin in plasma and tissues were below the MICs for the inoculated strain during infection. The treatment also reduced inflammatory responses to killed pneumococci in the lungs. These results suggest that the modification by roxithromycin of airway inflammatory responses, including those of matrix metalloproteinase-7 and phagocytes, is beneficial for initial resistance to macrolide-resistant pneumococci.

scholarly journals Live Attenuated Influenza Virus Expressing Human Interleukin-2 Reveals Increased Immunogenic Potential in Young and Aged Hosts

2006 ◽  
Vol 80 (23) ◽  
pp. 11621-11627 ◽  
Author(s):  
Boris Ferko ◽  
Christian Kittel ◽  
Julia Romanova ◽  
Sabine Sereinig ◽  
Hermann Katinger ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Young Adult ◽  
Influenza A ◽  
Interleukin 2 ◽  
Influenza Vaccines ◽  
Wild Type Virus ◽  
Considerable Proportion ◽  
Aged Mice ◽  
Adult Mice

ABSTRACT Despite the reported efficacy of commercially available influenza virus vaccines, a considerable proportion of the human population does not respond well to vaccination. In an attempt to improve the immunogenicity of live influenza vaccines, an attenuated, cold-adapted (ca) influenza A virus expressing human interleukin-2 (IL-2) from the NS gene was generated. Intranasal immunization of young adult and aged mice with the IL-2-expressing virus resulted in markedly enhanced mucosal and cellular immune responses compared to those of mice immunized with the nonrecombinant ca parent strain. Interestingly, the mucosal immunoglobulin A (IgA) and CD8+ T-cell responses in the respiratory compartment could be restored in aged mice primed with the IL-2-expressing virus to magnitudes similar to those in young adult mice. The immunomodulating effect of locally expressed IL-2 also gave rise to a systemic CD8+ T-cell and distant urogenital IgA response in young adult mice, but this effect was less distinct in aged mice. Importantly, only mice immunized with the recombinant IL-2 virus were completely protected from a pathogenic wild-type virus challenge and revealed a stronger onset of virus-specific CD8+ T-cell recall response. Our findings emphasize the potential of reverse genetics to improve the efficacy of live influenza vaccines, thus rendering them more suitable for high-risk age groups.

Abstract P106: The Role of Inflammasomes and Angiotensin II Type 1 Receptor in the Pressor Responses of Aged Mice to Angiotensin II

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Quynh N Dinh ◽  
Grant R Drummond ◽  
Barbara K Kemp-Harper ◽  
Henry Diep ◽  
Avril A Robertson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Renin Angiotensin System ◽  
Low Grade ◽  
Ang Ii ◽  
Contractile Responses ◽  
Aged Mice ◽  
Pressor Responses ◽  
Young Mice

Introduction: The prevalence of hypertension increases with age. Chronic low-grade inflammation commonly occurs with ageing, and inflammasomes are important initiators of inflammatory responses. We tested whether aged mice have enhanced pressor responses to angiotensin II (Ang II) and whether this is associated with exaggerated pro-inflammatory and vascular contractile responses. We also tested whether MCC950, a NLRP3 inflammasome inhibitor, reduces blood pressure (BP) in Ang II-treated aged mice. Methods: Young (8-12 weeks) and aged (24-30 months) male C57Bl6 mice were left untreated, or either treated with vehicle or a slow-pressor dose of Ang II (0.28 mg/kg/day) for 28 days. Another group of aged mice were treated with either Ang II + saline or Ang II + MCC950 (10 mg/kg/day) for 10 days. We measured systolic BP, mRNA expression of inflammatory markers and components of the renin-angiotensin system, and vascular contractile responses. Results: In young mice, Ang II caused a gradual increase in BP (final BP: 141.6 ± 8.3 mmHg), whereas BP increased by ~20 mmHg from baseline in aged mice, and continued to increase for 28 days (final BP: 155 ± 12.4 mmHg) (n=8-9, P<0.05). Ageing alone increased renal expression of AT1a receptors, NLRP3, Caspase-1, IL-1β, IL-33, CCR2, CCL7 and CCL8 by at least 1.5-fold (n=7-8, all P<0.05). Maximum contractile responses of mesenteric artery were 1.8-fold greater to Ang II and 1.2-fold greater to phenylephrine in aged vs young mice (n=4, both P<0.05). BP was not different between Ang II + saline-treated aged mice (BP: 138.8 ± 6.8 mmHg) and Ang II + MCC950-treated aged mice (BP: 144.7 ± 9.6 mmHg) (n=6-7, P>0.05). Conclusions: Aged mice have enhanced pressor responses to Ang II and this is associated with exacerbated pro-inflammatory and vascular contractile responses. The NLRP3 inflammasome does not appear to contribute to Ang II-induced hypertension in aged mice.

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