scholarly journals Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5918-5927 ◽  
Author(s):  
Ramona S. Scotland ◽  
Melanie J. Stables ◽  
Shimona Madalli ◽  
Peter Watson ◽  
Derek W. Gilroy
Keyword(s):  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Phenotype ◽  
Macrophage Phenotype ◽  
Blood Leukocytes ◽  
Bacterial Killing ◽  
Female Resident ◽  
Cytokine Levels ◽  
Lymphocyte Populations

Abstract Females are protected against mortality arising from severe sepsis; however, the precise mechanisms that confer this survival advantage in females over males are unclear. Resident leukocytes in resting tissues have a significant influence on circulating cytokine levels and recruitment of blood leukocytes during acute inflammatory responses. Whether the phenotype of resident leukocytes is distinct in females is unknown. In the present study, we show that the numbers of leukocytes occupying the naive peritoneal and pleural cavities is higher in female than in male mice and rats, comprising more T and B lymphocytes and macrophages. The altered immune cell composition of the female peritoneum is controlled by elevated tissue chemokine expression. Female resident macrophages also exhibit greater TLR expression and enhanced phagocytosis and NADPH oxidase–mediated bacterial killing. However, macrophage-derived cytokine production is diminished by proportionally more resident immunomodulatory CD4+ T lymphocytes. Ovarian hormones regulate macrophage phenotype, function, and numbers, but have no significant impact on T-lymphocyte populations in females. We have identified a fundamental sex difference in phenotype of resident leukocytes. We propose that the distinct resident leukocyte population in females allows aggressive recognition and elimination of diverse infectious stimuli without recruitment of circulating neutrophils or excessive cytokine production.

scholarly journals Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 372 ◽  
Author(s):  
Karl J. Harber ◽  
Kyra E. de Goede ◽  
Sanne G. S. Verberk ◽  
Elisa Meinster ◽  
Helga E. de Vries ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Phenotype ◽  
Independent Manner ◽  
Inflammatory Macrophages ◽  
Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

scholarly journals Delayed Addition of Glucocorticoids Selectively Suppresses Cytokine Production in Stimulated Human Whole Blood

2010 ◽  
Vol 17 (6) ◽  
pp. 979-985 ◽  
Author(s):  
Devin L. Horton ◽  
Daniel G. Remick
Keyword(s):  
Whole Blood ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Human Whole Blood ◽  
Proinflammatory Mediators ◽  
Cytokine Levels ◽  
Tlr4 Agonist ◽  
Cytokine Inhibitors ◽  
Toll Like Receptor 2

ABSTRACT Glucocorticoids (GC) are potent drugs proven to effectively treat inflammatory diseases, although patients typically begin therapy after the onset of symptoms. Clinical studies with cytokine inhibitors prove that these mediators drive inflammatory responses in diseases such as rheumatoid arthritis and Crohn's disease. Despite the clear sequence of cytokine-induced inflammation followed by effective GC treatment, most basic science investigations have examined the ability of GC to prevent an inflammatory response rather than halt its progression. The current studies used the Toll-like receptor 2 (TLR2) agonist palmitoyl3-cysteine-serine-lysine4 (PAM) or the TLR4 agonist lipopolysaccharide (LPS) to stimulate human whole blood and determine whether postponing the addition of the GC dexamethasone (DEX) limits its ability to decrease cytokine production. Twenty-four hours after stimulation, tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, and IL-8 levels were measured, in addition to the cytokine inhibitors IL-1 soluble receptor II (SRII), IL-1 receptor antagonist, and TNF SRII. LPS rapidly induced all of the proinflammatory mediators over 24 h while failing to induce any of the cytokine inhibitors. PAM stimulation also induced IL-1β, IL-6, and IL-8. Concomitant addition of DEX plus LPS or PAM significantly suppressed all cytokine levels. Delaying the addition of DEX until 6 h after LPS stimulation failed to decrease TNF or IL-6. In contrast, delayed DEX addition significantly suppressed PAM-induced IL-1β, IL-6, or IL-8 and also suppressed LPS-induced IL-1β and IL-8. Our results show that cytokines which typically increase in concentration between 6 and 24 h after stimulation were significantly suppressed by the addition of DEX 6 h after stimulation.

scholarly journals Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

2013 ◽  
Vol 57 (11) ◽  
pp. 5366-5372 ◽  
Author(s):  
Shiou-Ling Lu ◽  
Chiau-Yuang Tsai ◽  
Yueh-Hsia Luo ◽  
Chih-Feng Kuo ◽  
Wei-Chieh Lin ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Streptococcal Toxic Shock Syndrome ◽  
Local Infection ◽  
Skin Damage ◽  
Bacterial Killing ◽  
Local Skin ◽  
Group A ◽  
Anti Inflammatory

ABSTRACTGroup A streptococcus (GAS) infection may cause severe life-threatening diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Despite the availability of effective antimicrobial agents, there has been a worldwide increase in the incidence of invasive GAS infection. Kallistatin (KS), originally found to be a tissue kallikrein-binding protein, has recently been shown to possess anti-inflammatory properties. However, its efficacy in microbial infection has not been explored. In this study, we transiently expressed the human KS gene by hydrodynamic injection and investigated its anti-inflammatory and protective effects in mice via air pouch inoculation of GAS. The results showed that KS significantly increased the survival rate of GAS-infected mice. KS treatment reduced local skin damage and bacterial counts compared with those in mice infected with GAS and treated with a control plasmid or saline. While there was a decrease in immune cell infiltration of the local infection site, cell viability and antimicrobial factors such as reactive oxygen species actually increased after KS treatment. The efficiency of intracellular bacterial killing in neutrophils was directly enhanced by KS administration. Several inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1β, and interleukin 6, in local infection sites were reduced by KS. In addition, KS treatment reduced vessel leakage, bacteremia, and liver damage after local infection. Therefore, our study demonstrates that KS provides protection in GAS-infected mice by enhancing bacterial clearance, as well as reducing inflammatory responses and organ damage.

scholarly journals Lipid Nanoparticle Acts as a Potential Adjuvant for Influenza Split Vaccine without Inducing Inflammatory Responses

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 433
Author(s):  
Seiki Shirai ◽  
Atsushi Kawai ◽  
Meito Shibuya ◽  
Lisa Munakata ◽  
Daiki Omata ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Influenza Viruses ◽  
Inflammatory Cytokine Production ◽  
Virus Challenge ◽  
Aluminum Salts ◽  
Lipid Nanoparticle

Vaccination is a critical and reliable strategy for controlling the spread of influenza viruses in populations. Conventional seasonal split vaccines (SVs) for influenza evoke weaker immune responses than other types of vaccines, such as inactivated whole-virion vaccines, although SVs are highly safe compared to other types. Here, we assessed the potential of the lipid nanoparticle (LNP) we developed as an adjuvant for conventional influenza SV as an antigen in mice. The LNP did not induce the production of cytokines such as interleukin-6 (IL-6) and IL-12 p40 by dendritic cells or the expression of co-stimulatory molecules on these cells in vitro. In contrast, an SV adjuvanted with LNP improved SV-specific IgG1 and IgG2 responses and the Th1 response compared to the SV alone in mice. In addition, SV adjuvanted with an LNP gave superior protection against the influenza virus challenge over the SV alone and was as effective as SV adjuvanted with aluminum salts in mice. The LNP did not provoke inflammatory responses such as inflammatory cytokine production and inflammatory immune cell infiltration in mice, whereas aluminum salts induced inflammatory responses. These results suggest the potential of the LNP as an adjuvant without inflammatory responses for influenza SVs. Our strategy should be useful for developing influenza vaccines with enhanced efficacy and safety.

scholarly journals Macrophages rely on extracellular serine to suppress aberrant cytokine production

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kento Kurita ◽  
Hiroya Ohta ◽  
Ibuki Shirakawa ◽  
Miyako Tanaka ◽  
Yasuyuki Kitaura ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Immune Cell ◽  
De Novo ◽  
Inflammatory Responses ◽  
Culture Media ◽  
Expression Patterns ◽  
Interleukin 10 ◽  
Cell Functions ◽  
Mitochondrial Ros

AbstractA growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood. Here, we show that macrophages rely on extracellular serine to suppress aberrant cytokine production. Depleting serine from the culture media reduced the cellular serine content in macrophages markedly, suggesting that macrophages depend largely on extracellular serine rather than cellular synthesis. Under serine deprivation, macrophages stimulated with lipopolysaccharide showed aberrant cytokine expression patterns, including a marked reduction of anti-inflammatory interleukin-10 expression and sustained expression of interleukine-6. Transcriptomic and metabolomics analyses revealed that serine deprivation causes mitochondrial dysfunction: reduction in the pyruvate content, the NADH/NAD+ ratio, the oxygen consumption rate, and the mitochondrial production of reactive oxygen species (ROS). We also found the role of mitochondrial ROS in appropriate cytokine production. Thus, our results indicate that cytokine production in macrophages is tightly regulated by the nutritional microenvironment.

scholarly journals Evaluation of Berberine as an Adjunct to TB Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Mumin Ozturk ◽  
Julius E. Chia ◽  
Rudranil Hazra ◽  
Mohd Saqib ◽  
Rebeng A. Maine ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Late Onset ◽  
Communicable Disease ◽  
Synergistic Effects ◽  
Disease Stage ◽  
Adjunctive Treatment ◽  
Lung Pathology ◽  
Bacterial Killing ◽  
Inflammatory Status

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

scholarly journals SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8

2021 ◽  
Author(s):  
Valentina Salvi ◽  
Hoang Oanh Nguyen ◽  
Francesca Sozio ◽  
Tiziana Schioppa ◽  
Mattia Laffranchi ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Viral Genome ◽  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Dependent Lung ◽  
Molecular Patterns ◽  
Th1 Polarization ◽  
Myd88 Pathway

The inflammatory and IFN pathways of innate immunity play a key role in both resistance and pathogenesis of Coronavirus Disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-Associated Molecular Patterns (SAMPs) remain to be completely defined. Here we identify single-stranded RNA (ssRNA) fragments from SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and functions, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identify TLR7/8 as crucial cellular sensors of ssRNAs encoded by SARS-CoV-2 involved in host resistance and disease pathogenesis of COVID-19.

scholarly journals Arginase 1 is negatively regulated by β-catenin signaling in the lung

2017 ◽  
Author(s):  
Joseph A. Sennello ◽  
Annette S. Flozak ◽  
Alexander V. Misharin ◽  
Cara J. Gottardi ◽  
Anna P. Lam
Keyword(s):  
Cytokine Production ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Dietary Supplementation ◽  
Th2 Cytokines ◽  
Flow Cytometry Analysis ◽  
Wild Type ◽  
Arginase 1 ◽  
Cytokine Levels ◽  
Alternatively Activated

ABSTRACTWe previously demonstrated that mice lacking the Wnt co-receptor, Lrp5, had attenuated pulmonary fibrosis in the bleomycin model. We found that Arginase 1 (Arg1), an enzyme that converts L-arginine to urea and ornithine, was markedly elevated in Lrp5-/- lungs compared with wild-type mice after bleomycin injury. We show that this induction is not apparently due to the expression of Th2 cytokines, IL-4 and IL-13, but instead is due to Wnt/β-catenin signaling, which negatively regulates Arg1 expression in lung macrophages. Although Arg1 expression in macrophages has been used to define an alternatively activated phenotype, flow cytometry analysis of alveolar and interstitial macrophage sub-populations in Lrp5-/- lungs 14 days after bleomycin injury revealed no clear evidence of skewing from a classical to an alternatively activated phenotype. Upregulation of Arg1 expression and arginase activity might diminish lung arginine levels with consequent alterations in collagen or cytokine production. However, dietary supplementation of bleomycin-treated Lrp5-/- mice with the Arg1 substrate, L-arginine, failed to alter lung collagen content or cytokine levels 21 days after bleomycin injury. These findings demonstrate that Arg1 is negatively regulated by β-catenin signaling in macrophages, raising the possibility that Wnt signaling directs alterations in immune cell metabolism that may be relevant to lung repair after injury.

scholarly journals Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 and Spike Protein Subunit 1

2021 ◽  
Author(s):  
Theodore J. Cory ◽  
Russell S. Emmons ◽  
Johnathan R. Yarbro ◽  
Kierstin L. Davis ◽  
Brandt D. Pence
Keyword(s):  
Inflammatory Cytokines ◽  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Spike Protein ◽  
Glycolytic Metabolism ◽  
Protein Subunit ◽  
Pre Treatment

A hallmark of COVID-19 is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-α. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production in monocytes, and abrogated glycolytic and mitochondrial metabolism. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments in monocytes. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

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