HMGB1, an innate alarmin, in the pathogenesis of type 1 diabetes

Abstract

HMGB1, an evolutionarily conserved chromosomal protein, was recently re-discovered to act as a "danger signal" (alarmin) to alert the innate immune system for the initiation of host defense or tissue repair. Extracellular HMGB1 can be either passively released from damaged/necrotic cells or secreted by activated immune cells. Upon stimulation, dendritic cells (DCs), macrophages and natural killer (NK) cells secrete high levels of HMGB1 into the intercellular milieu. HMGB1 is potent to target DCs, macrophages, neutrophils and CD4(+) T cells. It also upregulates the expression of BCL-XL by which it may prevent the elimination of activated immune cells. As a result, HMGB1 has been suggested to be implicated in the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and experimental allergic encephalomyelitis (EAE). Given the similarities of autoimmune response against beta cell self-antigens in type 1 diabetes (T1D), in this view we will discuss the possible implications of HMGB1 in T1D pathogenesis. Specifically, we will summarize and update the advancement of HMGB1 in the pathogenesis of autoimmune initiation and progression during T1D development, as well as islet allograft rejection of diabetic patients after islet transplantation. Elucidation of the role for HMGB1 in T1D pathogenesis would not only enhance the understanding of disease etiology, but also have the potential to shed new insight into the development of therapeutic strategies for prevention or intervention of this disorder.

Keywords: HMGB1; innate alarmin; pathogenesis type 1 diabetes; review.

Figure 1

Sequence analysis showing evolutionary conservation of HMGB1 between diverse species. A: A phylogenetic tree showing evolutionary relationships of the HMGB1 gene between different species. The phylogenetic tree was constructed according to the calculation of the best match for the selected sequences. B: HMGB1 amino acid sequence alignment showing evolutionary conservation between diverse species. Sequence homology: black, 100% identical; pink, >75% identical; blue, >50% identical; and white, 0% identical.

Figure 2

Functional domains within the HMGB1 amino acid sequence. The full-length HMGB1 contains 2 homogenous domains (A- and B-box) and an acidic C-terminal tail. The B-box is associated with its properties relevant to proinflammatory activity and RAGE binding, while the A-box is a specific antagonist by which it inhibits the proinflammatory properties of HMGB1. The C-terminal acidic tail is required for transcription stimulatory function of HMGB1.

Figure 3

Altered beta-cell apoptosis during NOD physiological beta mass turnover after birth. A & B: TUNEL assay of pancreatic beta cell apoptosis during NOD and B6 neonate beta mass turnover. Insulin costaining indicates that the apoptotic cells are beta cells (A, the apoptotic cell is indicated by an arrow). C & D: Propidium Iodide (PI) staining of secondary necrotic beta cells in pancreatic sections originated from neonates undergoing beta mass turnover.

Figure 4

The immuno-regulatory properties for extracellular HMGB1. HMGB1 secretion by activated immune cells is indicated by blue arrows. Extracellular HMGB1 targets myeloid DCs, plasmacytoid DCs, macrophages, neutrophils and CD4⁺ T cells via the corresponding receptor(s) expressed on their surface. HMGB1 has also been found to up regulate the expression of BCL-XL, which may in turn prevent the elimination of activated autoreactive immune cells.