scholarly journals Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy

2021 ◽  
Vol 7 (26) ◽  
pp. eabh3693
Author(s):  
Theresa M. Raimondo ◽  
David J. Mooney
Keyword(s):  
T Cells ◽  
Muscle Function ◽  
Interleukin 4 ◽  
Muscular Dystrophies ◽  
Mdx Mice ◽  
Velocity Versus ◽  
Dystrophic Muscle ◽  
Cell Recruitment ◽  
Immune Phenotypes ◽  
Anti Inflammatory

Chronic inflammation contributes to the pathogenesis of all muscular dystrophies. Inflammatory T cells damage muscle, while regulatory T cells (Tregs) promote regeneration. We hypothesized that providing anti-inflammatory cytokines in dystrophic muscle would promote proregenerative immune phenotypes and improve function. Primary T cells from dystrophic (mdx) mice responded appropriately to inflammatory or suppressive cytokines. Subsequently, interleukin-4 (IL-4)– or IL-10–conjugated gold nanoparticles (PA4, PA10) were injected into chronically injured, aged, mdx muscle. PA4 and PA10 increased T cell recruitment, with PA4 doubling CD4+/CD8− T cells versus controls. Further, 50% of CD4+/CD8− T cells were immunosuppressive Tregs following PA4, versus 20% in controls. Concomitant with Treg recruitment, muscles exhibited increased fiber area and fourfold increases in contraction force and velocity versus controls. The ability of PA4 to shift immune responses, and improve dystrophic muscle function, suggests that immunomodulatory treatment may benefit many genetically diverse muscular dystrophies, all of which share inflammatory pathology.

scholarly journals Modulation of T Regulatory and Dendritic Cell Phenotypes Following Ingestion of Bifidobacterium longum, AHCC® and Azithromycin in Healthy Individuals

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2470
Author(s):  
Abeed H. Chowdhury ◽  
Miguel Cámara ◽  
Chandan Verma ◽  
Oleg Eremin ◽  
Anil D. Kulkarni ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Inflammatory Responses ◽  
Bifidobacterium Longum ◽  
Foxp3 Expression ◽  
Antibiotic Usage ◽  
Post Treatment ◽  
Interleukin 4 ◽  
Cytokine Profiles ◽  
Anti Inflammatory

The probiotic Bifidus BB536 (BB536), which contains Bifidobacterium longum, has been shown to have enhanced probiotic effects when given together with a standardized extract of cultured Lentinula edodes mycelia (AHCC®, Amino Up Co. Ltd., Sapporo, Japan). BB536 and AHCC® may modulate T cell and dendritic cell (DC) phenotypes, and cytokine profiles to favour anti-inflammatory responses following antibiotic ingestion. We tested the hypothesis that orally administered BB536 and/or AHCC®, results in modulation of immune effector cells with polarisation towards anti-inflammatory responses following antibiotic usage. Forty healthy male volunteers divided into 4 equal groups were randomised to receive either placebo, BB536, AHCC® or a combination for 12 days in a double-blind manner. After 7 days volunteers also received 250 mg azithromycin for 5 days. Cytokine profiles from purified CD3+ T cells stimulated with PDB-ionomycin were assessed. CD4+ CD25+ forkhead box P3 (Foxp3) expression and peripheral blood DC subsets were assessed prior to treatment and subsequently at 7 and 13 days. There was no difference in cytokine secretion from stimulated CD3+ T cells between treatment groups. Compared with baseline, Foxp3 expression (0.45 ± 0.1 vs. 1.3 ± 0.4; p = 0.002) and interferon-gamma/interleukin-4 (IFN-γ/IL-4) ratios were increased post-treatment in volunteers receiving BB536 (p = 0.031), although differences between groups were not significant. For volunteers receiving combination BB536 and AHCC®, there was an increase in myeloid dendritic cells (mDC) compared with plasmacytoid DC (pDC) counts (80% vs. 61%; p = 0.006) at post treatment time points. mDC2 phenotypes were more prevalent, compared with baseline, following combination treatment (0.16% vs. 0.05%; p = 0.002). Oral intake of AHCC® and BB536 may modulate T regulatory and DC phenotypes to favour anti-inflammatory responses following antibiotic usage.

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1742-1749 ◽  
Author(s):  
Antonella Cianferoni ◽  
John T. Schroeder ◽  
Jean Kim ◽  
John W. Schmidt ◽  
Lawrence M. Lichtenstein ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd4 T Cells ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Activated T Cells ◽  
Anti Inflammatory

Previous studies indicated that aspirin (acetylsalicylic acid [ASA]) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells. This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin (IL)-4 secretion and RNA expression in freshly isolated and mitogen-primed human CD4+ T cells. In contrast, ASA did not affect IL-13, interferon-γ, and IL-2 expression. ASA inhibited IL-4, but not IL-2, promoter-driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells. The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells, whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL-4 expression and promoter activity. The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor (NF)–κB and was accompanied by reduced binding of an inducible factor to an IL-4 promoter region upstream of, but not overlapping, the NF of activated T cells– and NF-κB–binding P1 element. It is concluded that anti-inflammatory salicylates, by means of a previously unrecognized mechanism of action, can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL-4, a critical effector of these responses, in CD4+ T cells.

scholarly journals Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Juan F. González ◽  
Jonathan Kurtz ◽  
David L. Bauer ◽  
Regan Hitt ◽  
James Fitch ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Salmonella Enterica ◽  
Systemic Disease ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Content Type ◽  
Chronic Carriage ◽  
Anti Inflammatory

ABSTRACT Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening systemic disease responsible for significant morbidity and mortality worldwide. Three to 5% of individuals infected with S. Typhi become chronic carriers due to bacterial persistence in the gallbladder. We have demonstrated that Salmonella forms biofilms on gallstones to establish gallbladder carriage. However, an in-depth molecular understanding of chronic carriage in the gallbladder, from the perspective of both the pathogen and host, is poorly defined. To examine the dynamics of the gallbladder in response to Salmonella infection, we performed transcriptional profiling in the mouse gallbladder at early (7 days) and chronic (21 days) time points. Transcriptome sequencing (RNA-Seq) revealed a shift from a Th1 proinflammatory response at 7 days postinfection (dpi) toward an anti-inflammatory Th2 response by 21 dpi, characterized by increased levels of immunoglobulins and the Th2 master transcriptional regulator, GATA3. Additionally, bioinformatic analysis predicted the upstream regulation of characteristic Th2 markers, including interleukin-4 (IL-4) and Stat6. Immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis confirmed a significant increase in lymphocytes, including T and B cells, at 21 dpi in mice with gallstones. Interestingly, the levels of Salmonella-specific CD4 T cells were 10-fold higher in the gallbladder of mice with gallstones at 21 dpi. We speculate that the biofilm state allows Salmonella to resist the initial onslaught of the Th1 inflammatory response, while yet undefined events influence a switch in the host immunity toward a more permissive type 2 response, enabling the establishment of chronic infection. IMPORTANCE The existence of chronic typhoid carriers has been in the public eye for over 100 years in part because of the publicity around Typhoid Mary. Additionally, it has been known for decades that the gallbladder is the main site of persistence and recently that gallstones play a key role. Despite this, very little is known about the physiological conditions that allow Salmonella enterica serovar Typhi to persist in the gallbladder. In this study, we analyze the transcriptional profile of the gallbladder in a mouse model of chronic carriage. We found a shift from an early proinflammatory immune response toward a later anti-inflammatory response, which could explain the stalemate that allows Salmonella persistence. Interestingly, we found a 10-fold increase in the number of Salmonella-specific T cells in mice with gallstones. This work moves us closer to understanding the mechanistic basis of chronic carriage, with a goal toward eradication of the disease.

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

scholarly journals Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhianna Jones ◽  
Kyle Kroll ◽  
Courtney Broedlow ◽  
Luca Schifanella ◽  
Scott Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Oral Microbiome ◽  
Probiotic Supplementation ◽  
Siv Infection ◽  
Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

scholarly journals Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
De-Huang Guo ◽  
Masaki Yamamoto ◽  
Caterina M. Hernandez ◽  
Hesam Khodadadi ◽  
Babak Baban ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Interleukin 4 ◽  
Hippocampal Synaptic Plasticity ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Dietary Obesity ◽  
Anti Inflammatory ◽  
Subcutaneous Adiposity ◽  
The Relationship

AbstractVisceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.

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