Homeostasis, Inflammation, and Disease Susceptibility

Abstract

While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation.

Disease tolerance and immunity in host protection against infection

“…Stress responses are triggered through the engagement of specific sensors that continuously monitor different physiological parameters under homeostatic regulation such as temperature, O 2 , pH, osmolarity, glucose and ATP [1][2][3] . When these parameters change beyond a certain threshold, "stress sensors" set off signal transduction pathways that alert cells for a possible disruption of homeostasis [1][2][3] .…”

“…When these parameters change beyond a certain threshold, "stress sensors" set off signal transduction pathways that alert cells for a possible disruption of homeostasis [1][2][3] . The ensuing stress responses provide metabolic adaptation in host cells, conferring tissue damage control and disease tolerance to infection 1-3 ( Figure 1&2).…”

“…Clinical signs and symptoms of infectious diseases emerge as host homeostasis [G] becomes compromised due to tissue dysfunction and damage [1][2][3] . Current understanding of this pathological process is limited, presumably impairing the ability to treat infectious diseases that remain associated with high human morbidity and mortality 4 .…”

Islet inflammation in type 2 diabetes

“…Classically, inflammation is a protective response, which involves many complex signals and aims to repair tissue and restore homeostasis [1]. However, dysregulated or prolonged inflammation states have been associated with many diseases, including type 2 diabetes [1].…”

“…Classically, inflammation is a protective response, which involves many complex signals and aims to repair tissue and restore homeostasis [1]. However, dysregulated or prolonged inflammation states have been associated with many diseases, including type 2 diabetes [1]. Early connections between inflammation, obesity and type 2 diabetes were made in the 1990s, in both rodent models and humans [2,3], and later substantiated by a large body of evidence (see [4][5][6][7] for recent reviews).…”