Distribution and storage of inflammatory memory in barrier tissues

Abstract

Memories of previous immune events enable barrier tissues to rapidly recall distinct environmental exposures. To effectively inform future responses, these past experiences can be stored in cell types that are long-term residents or essential constituents of tissues. There is an emerging understanding that, in addition to antigen-specific immune cells, diverse haematopoietic, stromal, parenchymal and neuronal cell types can store inflammatory memory. Here, we explore the impact of previous immune activity on various cell lineages with the goal of presenting a unified view of inflammatory memory to environmental exposures (such as allergens, antigens, noxious agents and microorganisms) at barrier tissues. We propose that inflammatory memory is distributed across diverse cell types and stored through shifts in cell states, and we provide a framework to guide future experiments. This distribution and storage may promote adaptation or maladaptation in homeostatic, maintenance and disease settings - especially if the distribution of memory favours cellular cooperation during storage or recall.

Figure 1 ∣. Cell type residence and permanence in barrier tissues.

The cell types in a tissue at any given moment may be there short-term (transient cells), have capacity to reside long-term in a tissue (resident cells) or be essential constituents (permanent resident cells). The fundamental permanent resident unit of a barrier tissue consists of epithelial stem cells and stromal cells (fibroblasts and endothelial cells). Other permanent resident cells include macrophages and sensory neurons. We acknowledge that there are specific cases where cell subsets that are typically transient (such as monocyte-derived mononuclear phagocytes) can acquire the characteristics of resident cells (such as Langerhans cells or macrophages) based on environmental perturbation and niche availability. Cell types that are non-essential to the fundamental tissue unit (plasma cells) can also exhibit characteristics of permanent residence. Moreover, microorganisms can also be permanent residents, residents or transient, and abiotic stimuli such as nutritional components can vary in “residence” based on the frequency and duration of environmental exposure.

Figure 2 ∣. Properties of tissue inflammatory memory storage.

a ∣ The properties of memory to a stimulus include increases in baseline, sensitivity, rapidity or maximum response. Graphic adapted with permission from REF. 11 © Elsevier. b ∣ The discrete components of tissue inflammatory memory storage include specificity, quantity, quality (i.e. cell state), durability and distribution among various cell types. Cooperativity may exist across similar or distinct cell types, with each cell type being defined through its own discrete components.

Figure 3 ∣. Inflammatory memory alters circuits in barrier tissues.

The flow of information through a naive tissue (a) or a hypothetical experienced tissue (b), in which memory has been established, with key regulators at each step highlighted on the side of the vertical flow. Arrows indicate predominant direction of information flow. By establishing memory in specific cell subsets such as antibody-producing plasma cells, resident memory CD8⁺ T cells and epithelial progenitors, the typical flow of information can be “inverted” in a tissue that has inflammatory memory.

Figure 4 ∣. Distribution and cooperation in tissue memory.

a ∣ A schematic illustrating that stromal, neuronal, epithelial and haematopoietic cells can contain distinct combinations of cell state modules which define their cell type, typical role in tissue maintenance, intrinsic immune capacity and inflammatory memory capacity. The presented values reflect hypothetical relative distributions. b ∣ Potential distributed inflammatory memory states for a system comprised of two cell types: (1) no memory; (2,3) one cell type or the other has inflammatory memory; (4,5) one cell type, or the other, has inflammatory memory which partially influences the other cell type; (6) both cell types collaborate in forming inflammatory memory; (7) or both cell types through cooperation can mutually reinforce one another.