Tissue Homeostasis and Inflammation

Abstract

There is a growing interest in understanding tissue organization, homeostasis, and inflammation. However, despite an abundance of data, the organizing principles of tissue biology remain poorly defined. Here, we present a perspective on tissue organization based on the relationships between cell types and the functions that they perform. We provide a formal definition of tissue homeostasis as a collection of circuits that regulate specific variables within the tissue environment, and we describe how the functional organization of tissues allows for the maintenance of both tissue and systemic homeostasis. This leads to a natural definition of inflammation as a response to deviations from homeostasis that cannot be reversed by homeostatic mechanisms alone. We describe how inflammatory signals act on the same cellular functions involved in normal tissue organization and homeostasis in order to coordinate emergency responses to perturbations and ultimately return the system to a homeostatic state. Finally, we consider the hierarchy of homeostatic and inflammatory circuits and the implications for the development of inflammatory diseases. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Fibroblasts and macrophages: Collaborators in tissue homeostasis

“…This is observed in the earliest metazoan tissues, like those of Placozoa, Ctenophora, Porifera, and Cnidaria, which consist of epithelial and mesenchymal cells 158,159 . In this basic tissue, epithelial cells create a barrier separating the internal environment from the external environment and the mesenchymal cells provide the tissue with structural integrity and organization 24 . This basic function of mesenchymal cells described here mirrors the earlier discussion of fibroblasts as structural cells.…”

“…In functional circuits where both cell types can sense the stimuli, existence of cell-cell communication can also allow for coordinated responses or tuning of a given response. 24 Fibroblasts and macrophages engage in both organizational and functional circuits. In the following section, a recently described organizational circuit between these two cell types in vitro will be discussed in more detail.…”

“…Taking all of these structural functions of fibroblasts into account, this fundamental and ubiquitous cell type can also be defined as a “supportive” cell within tissues. As recently discussed elsewhere, cells within a given tissue fall into two functional categories, (a) primary cells, responsible for performing the primary function of the tissue, and (b) supportive cells, responsible for performing supportive functions, which facilitate the execution of the primary function 24 . To illustrate this point, fibroblasts in the lung act to support proper organ functioning by providing ECM with structural properties that allow for continuous inspiration and expiration 25 …”

“…These diverse functions are regulated by distinct transcriptional and epigenetic programs, the details of which are currently being elucidated. Like fibroblasts, macrophages can also be defined as a “supportive” cells within tissues 24 . Macrophages perform a number of important accessory roles to support proper tissue functioning.…”

Gatekeepers of the Gut: The Roles of Proteasomes at the Gastrointestinal Barrier

“…Thus, an intricate regulatory network of host immune signaling and interactions is key for controlling and maintaining homeostasis at Biomolecules 2021, 11, 989 2 of 17 the gut. Yet, if regulatory mechanisms are breached, threatening conditions such as infection, inflammatory tissue damage, or cancer may arise [8][9][10][11]. Such diverse pathological outcomes require the consideration of different aspects of immune regulation: How do pathogens manipulate host regulators to evade immune responses?…”