Review of the mechanisms by which external factors, such as alcohol, cigarette smoke, air pollution, and others impact macrophage phagocytosis.
The ability of a pathogen to evade host immunity ...successfully, in contrast to the hostˈs capacity to defend itself against a foreign invader, is a complex struggle, in which eradication of infection is dictated by a robust immunologic response. Often, there are external factors that can alter the outcome by tipping the scale to benefit pathogen establishment rather than resolution by the hostˈs defense system. These external sources, such a cigarettes, alcohol, or environmental pollutants, can negatively influence the effectiveness of the immune systemˈs response to a pathogen. The observed suppression of immune function can be attributed to dysregulated cytokine and chemokine production, the loss of migratory potential, or the inability to phagocytose pathogens by immune cells. This review will focus on the mechanisms involved during the toxin‐induced suppression of phagocytosis. The accumulated data support the importance of studying the mechanisms of phagocytosis following exposure to these factors, in that this effect alone cannot only leave the host susceptible to infection but also promote alterations in many other macrophage functions necessary for pathogen clearance and restoration of homeostasis.
Summary Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not ...over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.
Advanced age impairs macrophage polarization Mahbub, Shegufta; Deburghgraeve, Cory R; Kovacs, Elizabeth J
Journal of interferon & cytokine research
32, Številka:
1
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Aging affects many aspects of the cellular function of macrophages. Macrophages play a critical role in innate immunity, acting as sentinels to fight pathogens, promoting wound healing, and ...orchestrating the development of the specific acquired immune response. However, little is known about how age influences the ability of macrophage to change phenotypes in response to environmental factors. This study examined the age-associated defects on macrophage polarization toward a pro-inflammatory (M1) or an anti-inflammatory (M2) phenotype. Adherent splenocytes enriched for macrophages were cultured with or without lipopolysaccharide (LPS), a combination of interferon (IFN)-γ and tumor necrosis factor (TNF)-α or interleukin (IL)-4. A panel of M1 markers, inducible nitric oxide synthase (iNOS), IL-6, IL-1β, and TNF-α, and M2 markers, including arginase-1 (Arg1), Ym1, and Found In Inflammatory Zone 1 (FIZZ1), were analyzed. IL-6 mRNA in cells from aged mice was decreased by 78% and 58% compared with young after stimulation with LPS or IFN-γ and TNF-α (P<0.05), respectively. Also, there was a marked reduction in the induced levels of iNOS, IL-1β, and TNF-α in cells from aged mice relative to young controls. Similarly, IL-4 exposure resulted in a reduction of M2 markers in adherent splenocytes from aged mice compared with younger animals. This was consistent with a 28% decrease in splenic F4/80(+)IL-4R(+) cells in aged mice relative to controls, although IL-4R expression on these cells did not vary between age groups. In contrast, levels of M1 and most M2 markers, save for FIZZ1, in bone marrow-derived macrophages were similar between the age groups, irrespective of stimuli. These data imply that impaired macrophage polarization in the elderly may dysregulate the development of the host response, making them more susceptible to infectious diseases and that the aging microenvironment may be a key modulator of these macrophage-elicited responses.
The aging lung Lowery, Erin M; Brubaker, Aleah L; Kuhlmann, Erica ...
Clinical interventions in aging,
01/2013, Letnik:
8
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There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in ...the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction. Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older. With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.
Aging and innate immune cells Plackett, Timothy P.; Boehmer, Eric D.; Faunce, Douglas E. ...
Journal of leukocyte biology,
August 2004, Letnik:
76, Številka:
2
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The innate immune system serves an important role in preventing microbial invasion. However, it experiences significant changes with advancing age. Among the age‐associated changes are: Aged ...macrophages and neutrophils have impaired respiratory burst and reactive nitrogen intermediates as a result of altered intracellular signaling, rendering them less able to destroy bacteria. Aged neutrophils are also less able to respond to rescue from apoptosis. Aged dendritic cells (DC) are less able to stimulate T and B cells. The altered T cell stimulation is a result of changes in human leukocyte antigen expression and cytokine production, and lower B cell stimulation is a result of changes in DC immune complex binding. Natural killer (NK) cells from the elderly are less capable of destroying tumor cells. NK T cells increase in number and have greater interleukin‐4 production with age. Levels of various complement components are also altered with advancing age.
Review on macrophage regulation and extracellular traps: implications in health and disease.
MΦ are multipurpose phagocytes with a large repertoire of well‐characterized abilities and functions, ...including regulation of inflammation, wound healing, maintenance of tissue homeostasis, as well as serving as an integral component of the innate‐immune defense against microbial pathogens. Working along with neutrophils and dendritic cells, the other myeloid‐derived professional phagocytes, MΦ are one of the key effector cells initiating and directing the host reaction to pathogenic organisms and resolving subsequent responses once the threat has been cleared. ETs are a relatively novel strategy of host defense involving expulsion of nuclear material and embedded proteins from immune cells to immobilize and kill bacteria, fungi, and viruses. As research on ETs expands, it has begun to encompass many immune cell types in unexpected ways, including various types of MΦ, which are not only capable of generating METs in response to various stimuli, but recent preclinical data suggest that they are an important agent in clearing ETs and limiting ET‐mediated inflammation and tissue damage. This review aims to summarize historical and recent findings of biologic research regarding ET formation and function and discuss the role of MΦ in ET physiology and associated pathologies.
Age‐related changes in immunity render elderly individuals more susceptible to infections than the young. Previous work by our laboratory and others showed that macrophages from aged mice are ...functionally impaired. Macrophages produce proinflammatory cytokines, tumor necrosis factor α (TNF‐α) and interleukin (IL)‐6, when stimulated with lipopolysaccharide (LPS), which signals through Toll‐like receptor‐4 (TLR4) and requires activation of mitogen‐activated protein kinases (MAPKs). We investigated whether aging is associated with alterations in TNF‐α and IL‐6 production and MAPK expression and activation in thioglycollate‐elicited peritoneal macrophages from mice. Kinetics and LPS dose‐responsiveness of macrophage TNF‐α production did not differ by age. Unstimulated macrophages did not differ by age in their cytokine production. However, LPS‐stimulated (100 ng/mL) cultures from aged mice produced 100 ± 30 pg/mL TNF‐α and 6000 ± 2000 pg/mL IL‐6, and those from young mice produced 280 ± 50 pg/mL and 10,650 ± 10 pg/mL, respectively (P<0.05). Likewise, levels of activated MAPKs did not differ by age in unstimulated macrophages, and LPS‐stimulated macrophages from aged mice had <70% activated p38 and c‐jun NH2‐terminal kinase (JNK) than those of young controls. Of particular interest, we observed >25% reduction of total p38 and JNK in macrophages from aged mice relative to young. In addition, surface TLR4 levels did not vary with age. We conclude that macrophages from aged mice exhibited suppressed proinflammatory cytokine production, which correlated with diminished total levels and LPS‐stimulated activation of p38 and JNK. These observations suggest that decreased MAPK expression could be a mechanism responsible for age‐related deterioration of the immune system.
The incidence of chronic wounds is increased among older adults, and the impact of chronic wounds on quality of life is particularly profound in this population. It is well established that wound ...healing slows with age. However, the basic biology underlying chronic wounds and the influence of age‐associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The impact of age and accompanying multi‐morbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables, lack of standardization in data collection, and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this paper, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify key research questions to guide future study of age‐associated changes in chronic wound healing.
Alcohol, aging, and innate immunity Boule, Lisbeth A.; Kovacs, Elizabeth J.
Journal of leukocyte biology,
July 2017, Letnik:
102, Številka:
1
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Review of aging and alcohol: how innate immunity is modulated in the aged and after alcohol consumption.
The global population is aging: in 2010, 8% of the population was older than 65 y, and that is ...expected to double to 16% by 2050. With advanced age comes a heightened prevalence of chronic diseases. Moreover, elderly humans fair worse after acute diseases, namely infection, leading to higher rates of infection‐mediated mortality. Advanced age alters many aspects of both the innate and adaptive immune systems, leading to impaired responses to primary infection and poor development of immunologic memory. An often overlooked, yet increasingly common, behavior in older individuals is alcohol consumption. In fact, it has been estimated that >40% of older adults consume alcohol, and evidence reveals that >10% of this group is drinking more than the recommended limit by the National Institute on Alcohol Abuse and Alcoholism. Alcohol consumption, at any level, alters host immune responses, including changes in the number, phenotype, and function of innate and adaptive immune cells. Thus, understanding the effect of alcohol ingestion on the immune system of older individuals, who are already less capable of combating infection, merits further study. However, there is currently almost nothing known about how drinking alters innate immunity in older subjects, despite innate immune cells being critical for host defense, resolution of inflammation, and maintenance of immune homeostasis. Here, we review the effects of aging and alcohol consumption on innate immune cells independently and highlight the few studies that have examined the effects of alcohol ingestion in aged individuals.
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