Recent developments in the role of high-mobility group box 1 in systemic lupus erythematosus

Abstract

High-mobility group box 1 (HMGB1) is an important molecule for several nuclear processes. Recently, HMGB1 has gained much attention as a damage-associated molecular pattern (DAMP) and has been implicated in the pathogenesis of several (auto)-immune diseases, in particular, systemic lupus erythematosus (SLE). A main pathogenic feature in SLE is the accumulation of apoptotic cells. Since HMGB1 is released from apoptotic cells it has been hypothesized that HMGB1 might fuel the inflammatory processes, as seen in this disease, and play a fundamental role in the pathogenesis. In this review, we discuss evidence in support of the theory that HMGB1 is an important mediator in SLE and may be considered a new autoantigen.

Figure 1

Role of HMGB1 in pathogenesis of SLE. In SLE, release of HMGB1 can occur via different routes: first, HMGB1 can be released from activated cells in an inflammatory environment; second, in SLE, apoptotic cells are not cleared properly because of impaired phagocytosis, which can lead to necrotic cells, which in turn release HMGB1; third, in SLE, low-density granulocytes are present that can spontaneously form NET (neutrophil extracellular traps), a process that leads to externalization of cellular content including HMGB1. In circulation or at inflammatory sites, HMGB1 can form complexes with DNA, nucleosomes, LPS or cytokines. HMGB1 alone or in complex can induce inflammation, for instance, in the kidney or in the skin of lupus patients (4), which in turn can lead to production of inflammatory cytokines. Also, complexed HMGB1 can activate plasmacytoid dendritic cells to produce IFN-α (5), a driving cytokine in lupus pathogenesis. Lastly, complexed HMGB1 can stimulate B-cells to produce autoantibodies (6). These activations lead to an inflammatory loop in which cytokines activate other cells, autoantibodies play a role in NETosis and HMGB1 itself can also induce NETosis and can play a role in the impaired phagocytosis. , HMGB1; , IFN-α; , inflammatory cytokines.