HMGB1 can serve as an alarmin. Alarmins are cellular molecules that promote inflammation and activate innate and adaptive immunity. In its activity as an alarmin, HMGB1 can interact with receptors that include receptor for advanced glycation end products (RAGE), and Toll-like receptors (TLR) 2, 4, and 9. There is increasing evidence that HMGB1 is involved in autoimmunity and chronic inflammation, as exemplified by increased levels of HMGB1 in the sera of patients with rheumatic disease. Recently, an association between the presence of HMGB1 and chronic renal diseases has been established, suggesting this protein has a role as a biomarker for assessing kidney outcome. In this review, we will discuss the biological properties of HMGB1 and summarize the recent advances on its role in inflammatory and chronic renal disease, including systemic lupus erythematosus.
Introduction
HMGB1 is a nonhistone nuclear protein that has attracted great interest as a protype for a dual-function molecule. Indeed, as shown in provocative in vitro and in vivo studies, HMGB1 has highly diverse biological properties that extend from DNA binding to transcriptional regulation to chromatin architecture and, most surprisingly, to immune activation. The study of this protein is providing an important new perspective on the biology of nuclear molecules and is illuminating the diversity of protein utilization in immune regulation. Furthermore, the study of HMGB1 is establishing the foundation for new approaches to monitor renal disease and develop novel immunosuppressive therapy.
HMGB1, which has a molecular mass of 30kD, is found in all mammalian tissues and is highly conserved in sequence among species. HMGB1 resides primarily in the cell nucleus but can be found in cytoplasm in certain types of cell. While the original literature on HMGB1 focused on its activity in the cell nucleus, a series of remarkable studies showed that HMGB1 can translocate to the outside of cells and, in the extracellular space, can serve as an alarmin. Alarmins are endogenous molecules, both large and small, that have the ability to alert the innate and adaptive immune system.1 HMGB1 is a prototypic alarmin that, once released into the extracellular space, can act as an inflammatory mediator in many rheumatic diseases, including systemic lupus erythematosus (SLE).2,3 This review will summarize the biological features of HMGB1 and its role as an inflammatory mediator in chronic kidney diseases. Moreover, this review will consider the role of HMGB1 in the pathogenesis of nephritis in SLE
HMGB1: Eternity Molecule with Many Functions
HMGB1 is a ubiquitous protein that is found in almost every type of cell in the body; however, not every cell is able to secrete HMGB1. Although HMGB1 secretion from immune cells has been widely described in literature, data from a variety of experimental systems indicate that that it can be also released from nonimmune cells. What is most surprising and intriguing about HMGB1 is that it has double life. Thus, HMGB1 has important biological functions inside as well as outside the cell, displaying highly distinct activities that encompass immune stimulation. This double life is based on the secretion and release of HMGB1 into the extracellular space during cellular activation and cellular death. While HMGB1 is actively secreted from activated immune-inflammatory cells such as monocytes and macrophages following stimulation with proinflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1, interferon [IFN]-γ) and bacterial products (lipopolysaccharide [LPS]), its release can also occur passively during necrosis as well as during the late phase of apoptosis (see Figure 1).4,5
