HMGB1: The Central Cytokine for All Lymphoid Cells

Abstract

High-mobility group box 1 (HMGB1) is a leaderless cytokine, like the IL-1 and FGF family members, that has primary roles within the nucleus and the cytosol. Within the nucleus, it serves as another guardian of the genome, protecting it from oxidant injury and promoting access to transcriptional complexes such as nuclear hormone/nuclear hormone receptors and p53/p73 complexes. Within the cytosol it promotes autophagy and recruitment of the myddosome to Toll-like receptor (TLR) 9 vesicular compartments. Outside of the cell, it can either bind to specific receptors itself, or with high affinity to DNA, nucleosomes, IL-1β, lipopolysaccharide, and lipoteichoic acid to mediate responses in specific physiological or pathological conditions. Currently identified receptors include TLR2, TLR4, the receptor for advanced glycation end products, CD24-Siglec G/10, chemokine CXC receptor 4, and TIM-3. In terms of its effects or functions within lymphoid cells, HMGB1 is principally secreted from mature dendritic cells (DCs) to promote T-cell and B-cell reactivity and expansion and from activated natural killer cells to promote DC maturation during the afferent immune response. Some studies suggest that its primary role in the setting of chronic inflammation is to promote immunosuppression. As such, HMGB1 is a central cytokine for all lymphoid cells playing a role complementary to its better studied role in myeloid cells.

Keywords: B cells; HMGB1; NK cells; RAGE; T cells; TLR2; TLR4; lymphocytes.

Figure 1

Differential expression of DAMP receptors for HMGB1 on lymphoid cells. Surprisingly, given the surfeit of receptors now shown to be expressed on various cell types, relatively little has been done to fully characterize the panoply of receptors on lymphoid cells. Best defined are the expression of RAGE on Ba and T-cells (but not to our knowledge on NK cells). Similarly TLR2, TLR4, CXCR4, and possible TIM-3 could play critical roles on subserving cell functions in response to HMGB1 on immune cells and this needs to be more carefully studied. Possible and defined roles are shown. “?” represents we hypothesize that HMGB1 binds to IL receptors, assisting in interleukin (cytokine) interaction. Also, expression of other HMGB1 receptors are unknown at present.

Figure 2

HMGB1 stimulates effector function from immune cells. In many instances, HMGB1’s function has been to subserve cell:cell interactions between lymphoid and myeloid cells. Its clearest definition has been with NK/macrophage or NK/DC interactions although suspected roles in B and T-cell activities are supported. What is unclear is whether these roles are cell type specific and whether HMGB1 might act in trans between a myeloid and lymphoid cell. “?” represents the state of uncertainty if HMGB1 plays a role in the setting of macrophage and NK cell interaction or HMGB1 is secreted from DCs to affect NK cell function.