Why does chronic inflammation persist: An unexpected role for fibroblasts

Abstract

One of the most important but as yet unanswered questions in inflammation research is not why inflammation occurs (we all get episodes of self limiting inflammation during the course of our lives) but why it does not resolve. Current models of inflammation stress the role of antigen-specific lymphocyte responses and attempt to address the causative agent. However, recent studies have begun to challenge the primacy of the leukocyte and have instead focused on an extended immune system in which stromal cells, such as fibroblasts play a role in the persistence of the inflammatory lesion. In this review I will illustrate how fibroblasts help regulate the switch from acute resolving to chronic persistent inflammation and provide positional memory during inflammatory responses. In chronic inflammation the normal physiological process of the removal of unwanted inflammatory effector cells becomes disordered, leading to the accumulation of leucocytes within lymphoid aggregates that resemble those seen in lymphoid tissue. I will describe how fibroblasts provide survival and retention signals for leukocytes leading to their inappropriate and persistent accumulation within inflamed tissue.

Fig. 1

A. Tertiary lymphoid structures, found in diseased tissues such as the rheumatoid synovium and thyroid gland share many features suggesting that similar subsets of fibroblasts may be involved in inflammation and immunity. B. During inflammation in peripheral tissues, fibroblasts become activated. Once inflammation resolves, these activated fibroblasts revert back to a resting state. It is suggested that in some cases fibroblasts in tissues may take on features of fibroblasts found in lymphoid tissues, and that these “ectopic” fibroblasts contribute to the formation of tertiary lymphoid structures.