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1.
Nat Commun ; 15(1): 4326, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773113

ABSTRACT

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.


Subject(s)
Dinoprostone , Disease Models, Animal , Lung , Macrophages , Mice, Inbred C57BL , Pneumonia, Pneumococcal , Receptors, Prostaglandin E, EP4 Subtype , Streptococcus pneumoniae , Animals , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/pathology , Pneumonia, Pneumococcal/microbiology , Pneumonia, Pneumococcal/metabolism , Mice , Dinoprostone/metabolism , Streptococcus pneumoniae/immunology , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/genetics , Macrophages/immunology , Macrophages/metabolism , Lung/immunology , Lung/pathology , Lung/microbiology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Integrin alpha Chains/metabolism , Integrin alpha Chains/genetics , Female , Antigens, CD/metabolism , Antigens, CD/genetics , T-Lymphocytes/immunology
3.
Nature ; 614(7947): 334-342, 2023 02.
Article in English | MEDLINE | ID: mdl-36697826

ABSTRACT

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.


Subject(s)
CD8-Positive T-Lymphocytes , Immune Tolerance , Lipopolysaccharide Receptors , Lipopolysaccharides , Liver , Myeloid Cells , Humans , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Lipopolysaccharide Receptors/metabolism , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasms/immunology , Neoplasms/pathology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Immune Tolerance/drug effects , Immune Tolerance/immunology , Liver/drug effects , Liver/immunology , Liver/pathology , Liver/virology , Interleukin-2/biosynthesis , Interleukin-2/immunology , Chemotaxis, Leukocyte , Bacteria/immunology , Intestines/immunology , Intestines/microbiology
4.
Nat Cell Biol ; 24(10): 1461-1474, 2022 10.
Article in English | MEDLINE | ID: mdl-36109671

ABSTRACT

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.


Subject(s)
Telomerase , Telomerase/genetics , Telomerase/metabolism , Immunologic Memory , T-Lymphocytes/metabolism , Telomere/genetics , Telomere/metabolism , Cellular Senescence/genetics
5.
BJGP Open ; 6(4)2022 Dec.
Article in English | MEDLINE | ID: mdl-36137647

ABSTRACT

BACKGROUND: Inflammation control is a fundamental part of chronic care in patients with a history of cancer and comorbidity. As the risk-benefit profile of anti-inflammatory drugs is unclear in survivors of cancer, GPs and patients could benefit from alternative non-pharmacological treatment options for dysregulated inflammation. There is a potential for home-built environment (H-BE) interventions to modulate inflammation; however, discrepancies exist between studies. AIM: To evaluate the effectiveness of H-BE interventions on cancer-associated inflammation biomarkers. DESIGN & SETTING: A systematic review and meta-analysis of randomised and non-randomised trials in community-dwelling adults. METHOD: PubMed and MEDLINE, Embase, Web of Science, and Google Scholar will be searched for clinical trials published in January 2000 onwards. The study will include H-BE interventions modifying air quality, thermal comfort, non-ionising radiation, noise, nature, and water. No restrictions to study population will be applied to allow deriving expectations for effects of the interventions in cancer survivors from available source populations. Outcome measures will be inflammatory biomarkers clinically and physiologically relevant to cancer. The first reviewer will independently screen articles together with GPs and extract data that will be verified by a second reviewer. The quality of studies will be assessed using the Cochrane risk-of-bias tools. Depending on the clinical and methodological homogeneity of populations, interventions, and outcomes, a meta-analysis will be conducted using random-effects models. CONCLUSION: Findings will determine the effectiveness of H-BE interventions on inflammatory parameters, guide future directions for its provision in community-dwelling survivors of cancer and support GPs with safer anti-inflammatory treatment options in high-risk patients for clinical complications.

6.
Nat Metab ; 4(4): 414-415, 2022 04.
Article in English | MEDLINE | ID: mdl-35361956

Subject(s)
Apoptosis , Inflammation , Humans
7.
Br J Clin Pharmacol ; 88(2): 680-690, 2022 02.
Article in English | MEDLINE | ID: mdl-34293819

ABSTRACT

AIMS: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies. METHODS: Eighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate. RESULTS: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24-hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)-6, IL-8 and tumour necrosis factor response followed by IL-1ß, IL-10 and interferon-γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells. DISCUSSION: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies.


Subject(s)
Lipopolysaccharides , Tumor Necrosis Factor-alpha , Cytokines/metabolism , Healthy Volunteers , Humans , Inflammation/chemically induced , Interleukin-6/metabolism , Male , Tumor Necrosis Factor-alpha/metabolism
8.
Clin Pharmacol Ther ; 111(4): 964-971, 2022 04.
Article in English | MEDLINE | ID: mdl-34935141

ABSTRACT

The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty-four healthy male volunteers received a two-and-a-half-day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two-and-a-half-day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti-inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti-inflammatory effects of such compounds in a minimally invasive manner.


Subject(s)
Clobetasol , Lipopolysaccharides , Adrenal Cortex Hormones , Anti-Inflammatory Agents/therapeutic use , Blister/drug therapy , Clobetasol/pharmacology , Clobetasol/therapeutic use , Cytokines , Drugs, Investigational , Erythema/drug therapy , Glucocorticoids/pharmacology , Healthy Volunteers , Humans , Male , Prednisolone/pharmacology
9.
JHEP Rep ; 3(6): 100332, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34825153

ABSTRACT

BACKGROUND & AIMS: Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction. METHODS: Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production. RESULTS: We show that hepatic production of PGE2 via the cyclo-oxygenase 1-microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)-DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor. CONCLUSIONS: PGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission. LAY SUMMARY: Patients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation.

10.
Nat Rev Immunol ; 21(10): 620-621, 2021 10.
Article in English | MEDLINE | ID: mdl-34580454
11.
FASEB J ; 35(10): e21913, 2021 10.
Article in English | MEDLINE | ID: mdl-34555204

ABSTRACT

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.


Subject(s)
Hydrogen Sulfide/metabolism , Inflammation/drug therapy , Naproxen/analogs & derivatives , Adolescent , Adult , Dinoprostone/metabolism , Escherichia coli/immunology , Escherichia coli/radiation effects , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/microbiology , Male , Middle Aged , Monocytes/cytology , Monocytes/drug effects , Monocytes/immunology , Naproxen/metabolism , Naproxen/pharmacology , Naproxen/therapeutic use , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/immunology , Pain/metabolism , Phenotype , Solubility , Ultraviolet Rays , Vasoconstriction/drug effects , Young Adult
12.
N Engl J Med ; 384(9): 808-817, 2021 03 04.
Article in English | MEDLINE | ID: mdl-33657293

ABSTRACT

BACKGROUND: Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown. METHODS: We conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment. RESULTS: A total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group. CONCLUSIONS: In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.).


Subject(s)
Albumins/therapeutic use , Liver Cirrhosis/therapy , Serum Albumin , Adult , Albumins/administration & dosage , Albumins/adverse effects , Ascites/etiology , Ascites/therapy , Female , Hospitalization , Humans , Infusions, Intravenous , Liver Cirrhosis/blood , Liver Cirrhosis/complications , Liver Cirrhosis/mortality , Liver Cirrhosis, Alcoholic/blood , Liver Cirrhosis, Alcoholic/therapy , Male , Middle Aged , Pulmonary Edema/etiology , Treatment Failure
13.
Pharmacol Ther ; 221: 107745, 2021 05.
Article in English | MEDLINE | ID: mdl-33188794

ABSTRACT

While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19 Drug Treatment , MAP Kinase Signaling System/drug effects , Pneumonia/drug therapy , Protein Kinase Inhibitors/therapeutic use , Respiratory Distress Syndrome/drug therapy , Anti-Inflammatory Agents/pharmacology , COVID-19/epidemiology , COVID-19/immunology , Clinical Trials as Topic/methods , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , MAP Kinase Signaling System/physiology , Pneumonia/epidemiology , Pneumonia/immunology , Protein Kinase Inhibitors/pharmacology , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/immunology
15.
Nat Immunol ; 21(6): 684-694, 2020 06.
Article in English | MEDLINE | ID: mdl-32231301

ABSTRACT

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cellular Senescence/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cytotoxicity, Immunologic , Gene Expression Profiling , Humans , Membrane Proteins/metabolism , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Nuclear Proteins/metabolism , Receptors, Antigen, T-Cell/metabolism , Receptors, Natural Killer Cell/metabolism , Signal Transduction , Yellow Fever/genetics , Yellow Fever/immunology , Yellow Fever/metabolism , Yellow Fever/virology , Yellow fever virus/immunology
16.
Nat Immunol ; 21(6): 696, 2020 06.
Article in English | MEDLINE | ID: mdl-32303726

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

17.
Nat Immunol ; 21(6): 615-625, 2020 06.
Article in English | MEDLINE | ID: mdl-32251403

ABSTRACT

Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.


Subject(s)
Inflammation/etiology , Inflammation/metabolism , Phagocytosis/immunology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Age Factors , Aged , Animals , Apoptosis , Blister/immunology , Blister/metabolism , Blister/pathology , Cantharidin , Gene Expression , Humans , Immunity, Innate , Inflammation/pathology , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/pathology , Receptors, Cell Surface/metabolism , Signal Transduction
18.
Nat Med ; 25(12): 1822-1832, 2019 12.
Article in English | MEDLINE | ID: mdl-31806905

ABSTRACT

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.


Subject(s)
Chronic Disease/epidemiology , Inflammation/physiopathology , Longevity/genetics , Autoimmune Diseases/etiology , Autoimmune Diseases/physiopathology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/physiopathology , Diabetes Mellitus/etiology , Diabetes Mellitus/physiopathology , Humans , Inflammation/complications , Inflammation/epidemiology , Life Style , Longevity/physiology , Neoplasms/etiology , Neoplasms/physiopathology , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/physiopathology , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/physiopathology , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/physiopathology , Risk Factors
19.
Trends Mol Med ; 25(3): 198-214, 2019 03.
Article in English | MEDLINE | ID: mdl-30795972

ABSTRACT

Deciphering the origins of chronic inflammatory and autoimmune diseases remains elusive with reliance on therapies aimed at halting inflammation in its tracks. In recent years, an appreciation of targeting pathways by which inflammation is resolved has begun to rouse interest. Resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of infection or injury to restore tissue function. However, recent studies suggest that resolution is not the end of innate mediated immune responses to infection/injury. There is further immunological activity occurring after the resolution cascade is complete that alters the immune physiology of tissues, redefining what was once termed restorative homeostasis as adapted homeostasis.


Subject(s)
Inflammation/etiology , Inflammation/metabolism , Acute Disease , Animals , Biomarkers , Chronic Disease , Cytokines/metabolism , Disease Susceptibility , Humans , Immunity , Inflammation/drug therapy , Inflammation/pathology , Inflammation Mediators/metabolism , Signal Transduction
20.
Br J Pharmacol ; 176(8): 1009-1023, 2019 04.
Article in English | MEDLINE | ID: mdl-30674066

ABSTRACT

We are all too familiar with the events that follow a bee sting-heat, redness, swelling, and pain. These are Celsus' four cardinal signs of inflammation that are driven by very well-defined signals and hormones. In fact, targeting the factors that drive this onset phase is the basis upon which most current anti-inflammatory therapies were developed. We are also very well aware that within a few hours, these cardinal signs normally disappear. In other words, inflammation resolves. When it does not, inflammation persists, resulting in damaging chronic conditions. While inflammatory onset is actively driven, so also is its resolution-years of research have identified novel internal counter-regulatory signals that work together to switch off inflammation. Among these signals, lipids are potent signalling molecules that regulate an array of immune responses including vascular hyper reactivity and pain, as well as leukocyte trafficking and clearance, so-called resolution. Here, we collate bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and their role in inflammation, as well as resolution. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.


Subject(s)
Lipids/immunology , Animals , Cytochrome P-450 Enzyme System/metabolism , Humans , Inflammation/enzymology , Inflammation/immunology , Lipids/biosynthesis , Prostaglandin-Endoperoxide Synthases/metabolism
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