HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins

Abstract

Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline-encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein (HMGB1), interleukin (IL)-1α, IL-33 and the Ca²⁺-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.

Figure 1

Role of HMGB1 in inflammation. Under resting conditions, HMGB1 is localized in the nucleus, where it plays an important role in chromatin structure and gene expression. The translocation of HMGB1 to the cytoplasm is regulated by post-translational modifications such as acetylation, methylation and phosphorylation (1). Because of the lack of a secretion signal, HMGB1 is actively secreted through a caspase-1-dependent, noncanonical secretory vesicular pathway (2). HMGB1 can also be passively released from damaged cells either alone or in complex with RNA, DNA or nucleosomes (3). Interestingly, during apoptotic cell death, ROS production induces the terminal oxidation of HMGB1 that inhibits its proinflammatory function and switches HMGB1 function toward tolerogenicity (4). Once in the extracellular space, HMGB1 binds to several receptors in either free or complexed form (5). HMGB1 receptors, including RAGE and TLR4, bind free HMGB1 or HMGB1 in complex with DNA or LPS. Through its interaction with RAGE, the internalization of the HMGB1–DNA complex increases the activation of TLR9 localized in the endosome. However, HMGB1 complex formation with nucleic acids and potentially with other molecules can be inhibited by direct interaction with TIM-3. Other receptors, such as TLR2, IL-1R and CXCR4, recruit HMGB1 in complex with nucleosomes, IL-1β or CXCL12, respectively. Thus, sensing of HMGB1 mediates mechanisms of inflammation, cell migration, proliferation and differentiation (6). Furthermore, acting through the CXCL12/CXR4 axis, HMGB1 enhances chemotaxis (7). HMGB1, high-mobility group box 1 protein; IL, interleukin; LPS, lipopolysaccharide; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; TLR, Toll-like receptor.

Figure 2

Proinflammatory role of extracellular interleukin (IL)-1α. IL-1α precursor (pIL-1α) is constitutively expressed in most resting nonhematopoietic cells. In these cells, IL-1α is primarily localized in the nucleus, where it promotes gene expression by acting as a transcription factor (1). IL-1α nuclear transport depends on its interaction with HS1-associated protein X-1 (HAX-1) (2). In stimulated cells, pIL-1α is processed by the membrane-bound protease calpain, a calcium-dependent cysteine protease, before active release into the extracellular space through a noncanonical vesicular pathway (3). Interestingly, HAX-1 was also found to interact with the cleaved IL-1α N-terminal domain, suggesting its independent nuclear function (2). pIL-1α processing is inhibited by the cytosolic expression of IL-1 receptor-2 (IL-1R2) that binds to pIL-1α and thereby prevents its interaction with calpain and its subsequent secretion (4). However, active caspase-1 cleaves IL-1R2 and thereby enables pIL-1α processing. pIL-1α can also be passively released from damaged cells and, similar to mature IL-1α, interacts with IL-1 receptor-1 (IL-1R1) (5). In addition to being released in the extracellular space, IL-1α can be displayed at the plasma membrane, where it activates IL-1R1-expressing juxtaposing cells (6). Once sensed by IL-1R1, soluble or membrane-bound IL-1α induces the recruitment of the accessory receptor IL-1R3 and triggers proinflammatory signaling pathways (7).

Figure 3

Extracellular role of interleukin (IL)-33. IL-33 is present in the nucleus of most stromal cells of tissues in contact with the environment. In the nucleus, IL-33 represses gene expression by facilitating chromatin compaction. Little is known concerning IL-33 translocation to the cytoplasm (1). IL-33 lacks a secretion signal and, therefore, active release may require packaging in noncanonical secretory vesicles (2). Processing by caspases inhibits the proinflammatory function of IL-33 (3). It is therefore likely that IL-33 is released in its full-length form either actively or passively following cell damage (4). However, in the extracellular space, cleavage of IL-33 by neutrophil cathepsin G or elastase promotes its proinflammatory activity (5). Both full-length and cleaved IL-33 interact with the ST2 receptor and further recruit the accessory receptor, IL-1 receptor-3 (IL-1R3), to trigger proinflammatory signals or T helper 2 (Th2)-type cell maturation and response (6). Interestingly, IL-33 extracellular function is regulated in time and space by rapidly occurring oxidation that inhibits its binding to ST2 (7).

Figure 4

Role of S100 protein in cell housekeeping and inflammation. S100 proteins are ubiquitously expressed in all cells and are crucial regulators of the calcium homeostasis machinery (1). The intracellular functions of S100 proteins also extend to specific cell functions such as transcriptional regulation and DNA repair (2), membrane protein recruitment and trafficking (3) and cytoskeleton assembly (4). The exact mechanisms that regulate the release of S100 proteins remain unclear thus far. Nevertheless, the secretion of S100 proteins occurs either passively upon cell damage or actively following cell activation (5). Once released into the extracellular space, S100 proteins interact with several receptors, most importantly RAGE and TLR4 (6). Upon binding to their receptors, S100 proteins trigger proinflammatory pathways promoting cell migration, proliferation and differentiation (7). S100 protein-induced signaling pathways also lead to the expression of MMPs and CAMs, thereby promoting chemotaxis and tissue remodeling (8). Certain S100 proteins, such as S100A8/A9, are extremely sensitive to oxidation (9). Their redox state acts as a molecular switch from proinflammatory function to protective wound-healing and antioxidant function. In return, oxidation-sensitive S100 proteins are believed to act as scavengers of ROS and NO and thereby prevent oxidative stress. CAM, cell adhesion molecule; MMP, matrix metalloproteinase; NO, nitric oxide; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; TLR4, Toll-like receptor 4.