Forkhead transcription factors in chronic inflammation

Forkhead (Fox) transcription factors have been increasingly recognized to play key roles in immune homeostasis, especially Foxp3 for its role in the development and function of regulatory T cells, and Foxo family members for their regulatory role in T and B lymphocytes as well as other leukocytes. Although these transcription factors positively regulate the expression of multiple target genes, a unique functional attribute of these genes is the maintenance of leukocyte homeostasis, such as the preservation of the naïve or quiescent T cell state and prevention of autoimmunity. As a result, many chronic inflammatory processes appear to reflect a relative loss of activity of one of these transcription factors, raising the possibility that therapeutic approaches which confer gain-of-function Fox activity may be beneficial. On the other hand, however, some of the Fox family members also appear to promote and/or maintain chronic inflammation by preserving inflammatory leukocyte survival and/or otherwise promoting the expression of inflammatory target genes, at least in some cell types such as neutrophils. Therefore, although the role of Fox in inflammatory disorders remains complex and incompletely understood, the continued study of these factors provides new insight into the initiation, maintenance, and propagation of inflammation.