Inflammation and Infection

To effectively defend against myriad microbial and environmental challenges, the inflammatory response must be able to respond to diverse stimuli by coordinating a limited array of sensory mechanisms and tissue responses. Successful inflammatory responses can limit host exposure to an inducer, eliminate it, or adapt to its presence. In most circumstances these responses are engaged at an appropriate level as determined by certain properties of the inducer and are resolved in a controlled manner. When these responses are aberrant in magnitude or duration they can have pathological consequences due to the fact that inflammatory responses operate at a cost to normal tissue function.

Acute inflammatory responses engage tissue responses in a manner which favors the elimination of the inducer. When an inducer such as tissue damage or infection is detected by PRRs on resident APCs, these sensor cells release inflammatory mediators that act both proximally and distally to induce changes to functional tissue states [1]. These mediators activate local endothelium to promote vasodilation, increased vascular permeability, and neutrophil infiltration, thereby enabling phagocytes and antimicrobial compounds to enter the infected area and eliminate the cause of inflammation. In the liver TNF and IL-6 act on hepatocytes, inducing a functional shift from the production of plasma proteins such as albumin to that of defensive compounds including C-reactive protein and complement. This rapid change enables large-scale release of antimicrobial compounds that can then enter inflamed tissues and act upon appropriate targets. In the brain these cytokines promote production of prostaglandins and cyclooxygenases, which override normal bodily functions to promote sickness behaviors including anorexia, fever, and behavioral depression [2]. Although the specific role of these behaviors is poorly understood they are believed to accelerate inducer clearance. TNF also induces insulin resistance in a broad range of host tissues, which is believed to enable redistribution of glucose to high priority cells including those of the immune system [3]. Following an acute insult the inflammatory response thus induces both local and systemic changes to normal tissue functionality in a coordinated effort that targets the inflammatory inducer for destruction.

When acute inflammation fails to eliminate the inducer or fails to resolve properly, it enters a chronic state to which the host must adapt via a distinct set of functional changes. Prolongation of an acute inflammatory response leads to a functional shift in inflammatory mediator production which serves to limit the collateral damage associated with chronic inflammation. These changes are mediated by feedback and epigenetic modifications, as in the case of epigenetic remodeling following TLR stimulation in order to prevent continual production of potentially damaging IL-6 while still allowing for the production of antimicrobial compounds [4]. In addition to alterations in the functional output of immune cells, there is a shift in the classes of cells recruited to the site of inflammation. While caustic neutrophils form the primary infiltrate during the acute response, a chronic response favors the recruitment of lymphocytes and macrophages which can clean up the debris left behind following neutrophil death, preventing further inflammatory induction and damage. These cells can also organize tertiary lymphoid organs which can sustain an inflammatory response. The presence of an inducer which is too large to be phagocytosed leads to a distinct form of adaptation known as the foreign body response, wherein macrophages attempting to engulf the inducer fuse together to form multinucleated granulomas. This process can limit ongoing inflammation by sequestering the inducer, shielding it from the surrounding tissues. The most effective adaptive inflammatory responses are able to manage a persistent state of inflammation by reducing the fitness costs associated with this chronic responsiveness while maintaining the necessary protective changes to normal tissue functionality. In essence a new homeostatic state is defined which is distinct from that which preceded the inducing event.

In addition to eliminating or adapting to an inflammatory inducer, the inflammatory response can work to limit host exposure to the inducer. Detection of an inflammatory inducer by IgE on mast cell surfaces leads to rapid degranulation and consequent release of histamine and other inflammatory mediators. Histamine acts on the smooth muscle of the bronchial and intestinal epithelium to promote constriction and peristalsis, on C-fiber neurons to produce an itching sensation, and on vascular endothelium to induce leakage enabling eosinophil infiltration. These functional changes can advance this response, promote inducer expulsion via vomiting or diarrhea, or prevent further inducer exposure via airway constriction and itching. In addition IL-13 induces goblet cell hyperplasia resulting in an increase in mucus production that bolsters barrier strength and ameliorates inducer removal. While each of these responses alone may fail to limit exposure to an inflammatory inducer, together they form a robust protective system that safeguards against noxious insults and alerts hosts to their presence. Alternative host responses can also limit exposure; enterochromaffin cells in the GI tract can respond to noxious compounds by releasing serotonin, which acts on proximal vagus nerves triggering symptoms of nausea and GI contraction [5]. The inflammatory response can thus alter the normal functionality of barrier tissues to promote rapid expulsion of the offending agent and prevent further uptake thereof.

The choice between these three pathways is complex, and certain properties of the inducing agent are key to this determination. When an inducer is detected on a surface contiguous with the external environment such as the skin, GI tract, or respiratory epithelium it has the potential to induce the functional changes associated with limiting inducer exposure and which are best suited to expelling an agent prior to its entry into the body. Localization is not the sole determinant of this pathway; upon secondary exposure, IgE-mediated modules will still instigate an allergic response even when an allergen is present within the circulatory system, as in the case of intravenously administered penicillin. Additionally most infections occur on or near the surface epithelium and yet induce an eliminatory inflammatory response, although localized barrier defenses such as mucus production are a common facet of such infections. Common allergens that are known to engage these defenses likely possess some low level of noxious activity which is detected by unknown sensory mechanisms in order to engage this pathway in sensitive individuals [6]. Indeed, the induction of barrier defenses to limit host exposure is likely the result of a confluence of inducer properties including proper initial localization, a lack of pathogen association, and some form of noxious activity which taken together provide the proper context to produce such a response.

The fact that no single property of an inducing agent will determine which of these three inflammatory responses are engaged is increasingly clear when attempting to establish what drives a response to be adaptive rather than eliminatory. Indeed, the same inflammatory inducers can drive either eliminatory or adaptive responses and the primary determinant of which is active is likely the duration of inflammatory challenge. If a new inducer is potentially harmful to a host and is recognized as such, the immediate inflammatory response will typically act to destroy the inducer. It is likely that an inducer will engage an eliminatory response simply by being recognized as an indicator of pathogenicity or damage that necessitates a coordinated response to restore tissue homeostasis. If this response is unsuccessful or fails to resolve then it may progress to a chronic adaptive form that seeks to define a new homeostatic condition. In many cases the initial cause of chronic inflammation is unknown, as in the case of obesity-associated inflammation, and it may be that the chronic noxious inflammatory state is secondary to an unknown process rather than to a single inflammatory event. Indeed the majority of current knowledge regarding the inducers of inflammation stems from the study of potent inducers that provoke high-grade inflammation, and it may be that there are many as of yet unknown properties of inducers of low-grade inflammation that promote an adaptive inflammatory response. Adaptive inflammation may also be favored when there is abundant collateral damage to improve tolerance.

While these inflammatory responses enable a return to homeostasis following a potentially dangerous encounter with an inflammatory inducer, each of these responses operates at a cost to normal tissue function. This cost is inevitable due to the fact that inflammation induces changes in a wide range of tissue functional states such that these tissues carry out their normal functions with reduced efficiency. This empowers the inflammatory response to bring about the broad changes necessary for its success, however it also introduces the potential for pathological consequences when normally homeostatic processes are misregulated in either duration or magnitude. The major pathological consequence of the inflammatory pathway that seeks to limit further host exposure to an inducing agent is the allergic response. The rapid kinetics and extreme IgE-mediated sensitivity of this response can, in severe cases, result in a sudden increase in mucus production and constriction of the airways leading to anaphylactic shock and death if left untreated. In less severe cases the result can be a potentially debilitating chronic rhinitis or an asthmatic response. In all cases pathology results from the fact that normally homeostatic mediators, such as histamine, are deleterious when induced at sufficient magnitude due to their ability to override normal tissue functionality.

In the case of an eliminatory response, much of the pathology again stems from a homeostatic response of inappropriate magnitude. In the case of septic shock, the same local alterations to tissue function that underlie a successful response disseminate throughout the body due to the presence of certain inflammatory inducers in the blood. These normally protective responses then become destructive, causing disseminated coagulation, altered body temperature, and a potentially severe drop in blood pressure due to vasodilation and vascular leakage leading to shock and death [7]. In susceptible individuals, a vigorous inflammatory response can also lead to abundant bystander tissue damage and self-reactivity resulting in autoimmune pathology. Additionally, while exudate formation enables clearance of inflammatory inducers in soft tissue, other organs such as the brain and joints have a much lower threshold for acceptable inflammatory levels, increasing their susceptibility to pathology.

The pathology associated with the adaptive inflammatory response is more subtle but can be serious if it occurs over an extended period. Inflammatory responses act on numerous tissues at a level dominant over normal homeostatic mechanisms so that when a threat is present the body will engage protective behaviors rather than respond normally to environmental cues. While some affected tissues will return to relatively normal functionality as the response progresses to a chronic state, those with multiple homeostatic set-points are vulnerable to being locked in an inflammatory conformation. The most salient example of such pathology is type II diabetes, in which tissues lose insulin responsiveness due to the constitutive engagement of the homeostatic pathway normally involved in redistributing glucose to high priority insulin-independent cells during an acute inflammatory response. Indeed, low-grade inflammation is predictive of T2D and obesity is believed to be associated with this inflammation [8]. As this example demonstrates, the pathology associated with chronic low-grade inflammation stems from the same adaptations which are beneficial during acute responses but which are harmful in a chronic state.

A successful inflammatory response requires molecular sensors to properly detect the magnitude and nature of the inflammatory inducer and to engage a response that addresses the threat and restores tissue homeostasis or defines a new homeostatic condition for a given tissue. In order to efficiently orchestrate this process the inflammatory response is able to operate at a level dominant and antagonistic to normal tissue functionality in situations where such activity is necessary to ensure survival. This allows inflammatory responses to limit exposure to noxious compounds, eliminate threats, and adapt to chronic insults as necessary for distinct inflammatory inducers. In certain scenarios these same dominant and antagonistic mechanisms can have serious pathological consequences stemming from inflammatory responses operating at an excessive magnitude or for an inappropriate duration. In these cases the reduction or alteration of normal tissue function due to damage or altered homeostatic control can cause systemic problems that underlie conditions including sepsis, allergies, and T2D. Future research will yield a more comprehensive understanding of the properties of inflammatory inducers that favor pathological outcomes, providing new avenues for therapeutic intervention and preventative treatment.

Inflammation and Aging

The aging process is complicated and is the result of a compilation of factors that arise over the life span of an organism, ultimately resulting in general deterioration and eventual death. Despite being a fundamental area of research interest for many labs and a fundamental fact of life for all of us, much of the aging process is still cloaked in mystery in a biological sense much as it is in a philosophical sense. From what we do understand of aging, it seems likely that many biological factors come into play, providing various insults against which the body must respond and restore homeostasis or adjust to a new state of homeostasis. While such adjustments may work well in the short term, over the entire life span of an organism these altered homeostatic set points can lead to debilitating states that no longer offer an advantage to the host organism. One such state that is commonly observed in older adults is a state of chronic inflammation - a symptom not only of aging, but of many other diseases of dysregulation from obesity to depression and beyond. Whether the initiation of aging linked inflammation is the same as the origin of other types of chronic inflammation is not known, however it is though that aging linked inflammation is a driver of the over all aging process, such that some models of aging are known as so called “inflammaging models”. These models posit that the gradual accumulation of inflammation in older adults results in positive feedback loops that encourage additional inflammation and consequent pathology, which manifests as some of the negative attributes of the aging process.

How aging related inflammation begins is a mystery, but there is some evidence to suggest that it may originate from several different factors that together orchestrate the ultimate inflammatory response. For example, over time through both random mutation and extracellular threats (such as UV radiation or chemical insults), the DNA of cells accumulates damage. Most of this damage will be repaired successfully to prevent the death of cells or the development of cancer, but some of this damage may alter gene expression in affected cells to promote a more inflammatory state. Such accumulation of damage is another part of common theories of aging, and one major source of DNA damage with age is thought to be reactive oxygen species (ROS) generated by the cells of aging individuals. ROS are the byproducts of cellular energy generation as well as a few other biological processes, and as such cells frequently produce these oxygen radicals every day. These molecules are, however, biologically very unstable and they will damage or destroy nearby proteins and DNA when they are not contained. For this reason, cells produce antioxidants that help control the oxidative damage to which cells are exposed.


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