Stroma: the forgotten cells of innate immune memory

Abstract

SummaryAll organisms are exposed constantly to a variety of infectious and injurious stimuli. These induce inflammatory responses tailored to the threat posed. While the innate immune system is the front line of response to each stimulant, it has been considered traditionally to lack memory, acting in a generic fashion until the adaptive immune arm can take over. This outmoded simplification of the roles of innate and acquired arms of the immune system has been challenged by evidence of myeloid cells altering their response to subsequent encounters based on earlier exposure. This concept of ‘innate immune memory’ has been known for nearly a century, and is accepted among myeloid biologists. In recent years other innate immune cells, such as natural killer cells, have been shown to display memory, suggesting that innate immune memory is a trait common to several cell types. During the last 30 years, evidence has slowly accumulated in favour of not only haematopoietic cells, but also stromal cells, being imbued with memory following inflammatory episodes. A recent publication showing this also to be true in epithelial cells suggests innate immune memory to be widespread, if under‐appreciated, in non‐haematopoietic cells. In this review, we will examine the evidence supporting the existence of innate immune memory in stromal cells. We will also discuss the ramifications of memory in long‐lived tissue‐resident cells. Finally, we will pose questions we feel to be important in the understanding of these forgotten cells in the field of innate memory.

The microbiome and immune memory formation

“…It remains to be seen whether epithelial stem cells at other barrier sites, such as the intestine, can also be induced to retain memory through modifications of the epigenetic landscape. Finally, stromal cells, which include fibroblasts and endothelial cells, also show memory to previous stimuli (reviewed in Reference ). Coculture of macrophages with LPS‐trained bone marrow‐derived mesenchymal stem cells in vitro led to reduced proinflammatory and enhanced anti‐inflammatory responses in the macrophages, which was associated with epigenetic alterations in the mesenchymal stem cells mesenchymal stem cells .…”

Time course analyses of structural changes in the infrapatellar fat pad and synovial membrane during inflammation-induced persistent pain development in rat knee joint

“…Previous studies suggested that synovial fibroblasts function as sentinel cells that can sense tissue damage in the joint [25]. The process of tissue damage recognition by synovial fibroblasts is considered to occur through binding of DAMPs (damage-associated molecular patterns) to their receptors, such as TLR4 (Toll-like receptor 4) [25, 26]. Engagement of TLR4 activates MyD88 (myeloid differentiation primary response protein 88) signaling pathways within synovial fibroblasts which induce the release of various pro-inflammatory cytokines and chemokines [25, 27].…”

Inflammation and immune resolution

“…In their review, Crowley et al . present compelling evidence for the existence of innate immune memory in stromal cells. The authors discuss how stromal memory may exacerbate or restrain inflammatory disease.…”

“…In recent years, the concept of innate immune memory, particularly in myeloid cells, has been catapulted into the limelight by the elegant work of Mihai Netea and coworkers. In their review, Crowley et al [3] present compelling evidence for the existence of innate immune memory in stromal cells. The authors discuss how stromal memory may exacerbate or restrain inflammatory disease.…”