Obesity- And Neuroinflammation: The Role Of Obesity In The Immune Response During Sepsis

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Fast Facts hopkinsmedicine.org JOHNS HOPKINS / EVIDENCE BASED MEDICINE Obesity- and Neuroinflammation: The role of obesity in the immune response during sepsis O besity is fast becoming the disease of the twenty-first century mainly due to its association with secondary disorders, most notably type 2 diabetes and cardiovascular disease, which are collectively known as metabolic syndrome (MetS). Obesity is known to reduce overall life expectancy and is associated with an increased incidence of chronic health conditions such as type two diabetes mellitus, hypertension, heart failure, and coronary artery disease. Overweight and obesity are now considered a worldwide pandemic and a growing public health problem with severe economic and social consequences. Adipose tissue is an organ with neuroimmune-endocrine functions, which participates in homeostasis. So, adipocyte hypertrophy and hyperplasia induce a state of chronic inflammation that causes changes in the brain and induce neuroinflammation. Studies with obese animal models and obese patients have shown a relationship between diet and cognitive decline, especially working memory and learning deficiencies. Neuropsychiatric comorbidity is more frequent in obese patients than in the general age-matched population. The overwhelming influence of metabolic and neuropsychiatric disorders considerably reduces the quality of life of these patients, increases morbidity and mortality rates, and results in incremental costs to health care systems around the world. Chronic obesity is often characterized by hypertension, coronary artery disease, dyslipidemia, and impaired glucose tolerance linked to hyperinsulinemia and insulin resistance, which are collectively defined as MetS. Along with metabolic dysregulations, basal low-grade inflammation increasingly appears as another key component of this condition. Sepsis is defined as the systemic inflammatory response syndrome attributed to infection. It is the leading cause of morbidity and mortality in noncardiac intensive care units worldwide and it is related with a high cost of care. Article notes This newsletter is one of the many ways we seek to enhance our partnership with our referring physicians. Comments, questions and thoughts on topics you would like to see covered in upcoming issues are always welcome. Y0200_HMO001EOC01020_C File & Use 09062022 In addition to peripheral organ dysfunction, increasing evidence suggests that obesity/MetS is also a risk factor for neurological disorders such as neuropsychiatric disorders (depression, anxiety, and cognitive impairments), stroke, and Alzheimer’s disease. Copyright © 2022 Medina Ortega; Saavedra Torres; Muñoz Samboni; Alegría Portilla; Zúñiga Cerón; Zambrano López; Erazo Paredes and Ledesma Herrera. Johns Hopkins Medicine Marketing and Communications 901 S. Bond St., Suite 550 Baltimore, MD 21231 Pathophysiology of sepsis, it is characterized by the activation of endothelial cells and monocytes and the initiation of inflammatory and coagulation cascades, in response to invading pathogens leading to collateral damage of normal tissues. Published online July 21, 2022. WRITE: Johns Hopkins Advantage MD P.O. Box 3538 Scranton, PA 18505 Disclaimer For questions or comments, contact: Lisa Eddy at [email protected] or 443-287-2527. ©2022 The Johns Hopkins University and The Johns Hopkins Health System Corporation. Sepsis induces activation of cerebral endothelial cells, which result in blood–brain barrier (BBB) dysfunction and release of various mediators into the brain. To learn more about the Johns Hopkins The immune response in sepsis is determined by many factors including co-morbidities (i.e., diabetes, heart disease, malignancy) as well as the pathogen virulence and size of the microbial inoculums. Although both pro- and anti-inflammatory processes are activated simultaneously during the onset of sepsis, during the first few days, a hyper-inflammatory response often dominates the clinical picture. Department of Physical Medicine and Rehabilitation, visit hopkinsmedicine.org/pmr. For referrals and consultations: Hopkins Access Line (HAL) 1-800-765-5447 or 410-955-9444 For CME Programs: hopkinscme.cloud-cme.com 410955-2959 [email protected] . Fast Facts: Johns Hopkins Medicine 1 SPECIAL EVIDENCE Copyright © 2022 Medina Ortega; Saavedra Torres; Muñoz Samboni; Alegría Portilla; Zúñiga Cerón; Zambrano López; Erazo Paredes and Ledesma Herrera. The elderly has a higher risk of developing sepsis than younger peoples. Under the influence of inflammatory mediators and oxidizing agents released in the periphery as a result of the infectious stimulus, changes occur in the blood-brain barrier (BBB) permeability, with neutrophil infiltration, the passage of toxic compounds, activation of microglia and production of reactive species that results in potentiation of neuroimmune response, with the progression of neuronal damage and neuroinflammation. It follows that obesity due to its pro-inflammatory phenotype can aggravate or accelerate the sepsis-induced damage in rat and human brain. Sepsis is a severe clinical syndrome in which a system-wide inflammatory response follows initial attempts to eliminate pathogens. It is not novel that in sepsis the brain is one of the first organs affected which causes an increase in morbidity and mortality and its consequences may be exacerbated when associated with a diagnosis of chronic inflammation, such as in obesity. Experimental data indicate that at the early phase of sepsis, endothelial nitric oxide synthase-derived nitric oxide exhibits proinflammatory characteristics and contributes to the activation and dysfunction of cerebrovascular endothelial cells. The hyper-inflammatory phase has been termed a “cytokine storm” that is indicated by increased levels of TNF-α, IL-1β, and IL-6. A robust depletion of both innate and adaptive immune cells through apoptosis occurs to dampen the response. Obesity promotes a chronic low-grade inflammatory state that develops following activation of resident macrophages in adipose tissue, promoting the recruitment of M1-polarized macrophages, which display a proinflammatory phenotype, increasing the local and systemic production of proinflammatory cytokines (TNFα, IL-6, and others). Macrophage polarization refers to the process by which macrophages produce distinct functional phenotypes as a reaction to specific microenvironmental stimuli and signals. Macrophages can be polarized into classically activated (M1) and alternatively activated (M2) macrophages. Perivascular adipose tissue (PVAT) surrounds most blood vessels except the cerebral vasculature, and is elevated in obesity. Noteworthy, PVAT is capable of interacting with inflammatory cells, the nervous system, and vascular cells to promote or modulate vascular disease. In physiological conditions, PVAT plays a fundamental role in vasodilation via production of adipokines, including adiponectin. Obesity leads to lowered levels of the antiinflammatory adipokine adiponectin in Circulation. The etiology of the "insulin resistance syndrome" caused by sepsis or metabolic syndrome is multifactorial, and the mechanisms underlying the intercorrelations among these metabolic conditions are not entirely clear. Although the involvement of adipose tissue hormones in the obesityinduced insulin resistance has been studied, there is only few information about its changes in critically ill patients. Under inflammatory states, such as obesity, vasodilatory adipokine release is diminished from inflamed, dysfunctional PVAT, thus promoting vasoconstriction. Leptin released from adipocytes can stimulate macrophages to produce proinflammatory cytokines. Immune cells infiltrating PVAT in obesity can also promote vasoconstriction and endothelial dysfunction via cross talk with vascular cells, suggesting that the crosstalk between immune cells and adipocytes may be an important feature driving a proinflammatory environment. Moreover, this is amplified (alarmingly) by the fact that neuropsychiatric disorders may reciprocally increase the risk for a pattern of physiological and biochemical dysregulations consistent with being overweight. Several studies have also demonstrated an increased risk of developing infection and sepsis with worse outcomes in infections compared to normal weight patients. Hyperglycemia and insulin resistance frequently occur in critically ill and in morbidly obese (MO) patients. Both conditions are associated with altered serum levels of cytokines and adipokines. In addition, obesity related alterations in adipokine expression contribute to insulin resistance in metabolic syndrome. The expressions of these adipokines and cytokines are changed in obese persons, since obesity is associated with the appearance of a chronic, low inflammatory state due to changes in adipocyte and macrophage function. Adiponectin is known to be a regulator of insulin sensitivity and glucose metabolism. Furthermore, hypoadiponectinemia has been shown to be associated with insulin resistance and hyperinsulinemia. Several studies have provided evidence that increased blood glucose levels impair morbidity and mortality in critically ill patients and that intensive insulin therapy aimed at maintaining euglycemia markedly improved the outcome of these patients. Obesity entails an increased proinflammatory, prothrombotic state associated with a hormonal rearrangement in a context of decreased cardio-respiratory fitness and limited respiratory capacity. Obesity Exacerbates Sepsis-Induced Oxidative Damage in Organs. Obesity is a mortality protector factor in sepsis; this phenomenon is known as «obesity paradox». Furthermore, obesity is a chronic inflammatory state in which adaptive and innate immunity mediators play key roles. Lymphopenia is an adaptive immunity marker and it has been related to poor outcomes and greater mortality. Obesity is a growing health problem and associated with immune dysfunction. Excessive inflammation combined with immune dysfunction can lead to multiorgan damage and death. . Fast Facts: Johns Hopkins Medicine 2 SPECIAL EVIDENCE Copyright © 2022 Medina Ortega; Saavedra Torres; Muñoz Samboni; Alegría Portilla; Zúñiga Cerón; Zambrano López; Erazo Paredes and Ledesma Herrera. ILLUSTRATION: Obesity- and Neuroinflammation: The role of obesity in the immune response during sepsis - all rights reserved: Department of emergency medicine, Colombia, South America. An increase in morbidity in obese septic patients compared with lean people is a cause of growing concern. Laboratory evidence suggests that there is exaggeration in the inflammatory and prothrombogenic phenotype assumed by obese compared with lean septic animals. The exact mechanisms underlying this phenomenon are unknown. This article originally appeared on hopkinsmedicine.org Author information 1 Marco Antonio Medina Ortega; 2Jhan S. Saavedra Torres; 3 Jorge Luis Muñoz Samboni; 4Diego F. Alegría Portilla; 5 Luisa F. Zúñiga Cerón; 6Esteban Darío Zambrano López; 7 Ivan Alejandro Erazo Paredes; and 8Angie Nathalia Ledesma Herrera. Cited By Vachharajani V, Vital S. Obesity and Sepsis. Journal of Intensive Care Medicine. 2006;21(5):287-295. doi:10.1177/0885066606290670 Aguilar-Valles, A., Kim, J., Jung, S., Woodside, B. & Luheshi, G.N. (2014) Role of brain transmigrating neutrophils in depression-like behavior during systemic infection. Molecular Psychiatry, 19 (5), 599–606. Vieira, A. A., Michels, M., Florentino, D., Nascimento, D. Z., Rezin, G. T., Leffa, D. D., Fortunato, J. J., Dal-Pizzol, F., Barichello, T., Quevedo, J., & Petronilho, F. (2015). Obesity promotes oxidative stress and exacerbates sepsisinduced brain damage. Current neurovascular research, 12(2), 147–154. https://doi.org/10.2174/1567202612666150311111 913 Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. 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