Stress, inflammation, and defense of homeostasis

Abstract

Inflammation is traditionally considered a defense response induced by infection or injury. However, inflammation can also be induced by tissue stress and malfunction in the absence of infection or overt tissue damage. Here we discuss the relationship between homeostasis, stress responses, and inflammation. Stress responses have cell-autonomous and cell-extrinsic components, the latter contributing to tissue level adaptation to stress conditions. Inflammation can be thought of as the extreme end of a spectrum that ranges from homeostasis to stress response to bona fide inflammatory response. Inflammation can be triggered by two types of stimuli: extreme deviations of homeostasis or challenges that cause a disruption of homeostasis. This perspective may help to explain qualitative differences and functional outcomes of diverse inflammatory responses.

FIGURE 1. An Inflammatory Spectrum

An inflammatory response is an extreme end of the spectrum that ranges from homeostatic state, to stress response, para-inflammation, and finally, inflammation.

FIGURE 2. Stress and Defense Response Components of Inflammation

Inflammation can be induced by sensing extreme deviations from tissue homeostasis or by sensing the challenges that can cause extreme deviations of tissue homeostasis. The former are detected by sensors of regulated variables of cellular and tissue homeostasis. The latter can be induced upon direct recognition of structural features of agents that can disrupt tissue homeostasis (e.g., PAMP recognition by PRRs) or by detecting their conserved functional features, such as protease activity or chemical reactivity.

FIGURE 3. Cell Autonomous and Non-Cell Autonomous Responses

Cellular stress and defense responses have two components – cell autonomous (i.e., intrinsic) and non-cell autonomous (i.e., extrinsic). The former controls intracellular adaptations, while the latter modifies the extracellular environment or communicates to neighboring parenchymal cells. Stress signals also act directly on specialized cells such as macrophages and sensory neurons. These ‘professionals’ are able to detect stress at a lower threshold than parenchymal cells, and they produce cytokines and growth factors to promote restoration of function. Stressed parenchymal cells also communicate with the specialized sensory cells through largely unknown paracrine factors.