CONTRIBUTION OF HMGB1 TO HUMAN DISEASES
Besides its crucial implication in acute conditions such as severe sepsis, HMGB1 has been implicated in the pathogenesis of several chronic inflammatory diseases or in pathologies where chronic local inflammation is important, such as atherosclerosis.
Some examples are presented below.Rheumatoid Arthritis
HMGB1 has been implicated in the development of rheumatoid arthritis. In animal models, HMGB1 is highly expressed in synovial tissue and fluid as well, and the symptoms are reduced by the administration of antibodies against
HMGB1 or by recombinant box-A [50]. Reversely, intra-articular injection of HMGB1 in healthy animals induces arthritis [51] whereas high levels of HMGB1 have been found in vivo, in the synovial fluid of patients with rheumatoid arthritis [52].
Cancer
HMGB1 is over-expressed in many tumor cells but the link between HMGB1 and cancer development is complex and still partially understood. This may be due at least in part to the ability of HMGB1 to modulate gene expression. In colon carcinomas for example, HMGB1 overexpression has been associated with a pronounced activation of NF-kB responsive genes, including c-IAP2, a protein that prevents apoptosis. In the same study, the authors were also able to correlate HMGB1 over expression to the reduced activity of two pro-apoptotic proteins, namely the caspase-3 and -9 [53].
As indicated before, numerous studies demonstrated that interaction between HMGB1 and RAGE promoted the growth, spread and metastasis of tumors from diverse origins, including colon and prostate [42,54]. Importantly, blockade of this interaction by soluble or mutated RAGE reversed tumor aggressiveness [55].
On the opposite, the adjuvant action of HMGB1 may be beneficial to the anti-tumoral immune response. Indeed, the release of HMGB1 by dying tumor cells after radiotherapy or chemotherapy can promote an efficient tumor antigen-specific immune responses, a process that involve HMGB1 recognition by TLR-4 at the surface of dendritic cells [56]. In the same respect, HMGB1 released by dying tumor cells may contribute to brain tumor regression, a process that is dependent of TLR-2 [57].
Atherosclerosis
Local chronic inflammation plays a key role in atherogenesis. Recent data demonstrated the expression of HMGB1 in activated vascular smooth muscle cells in human atherosclerotic lesions. HMGB1 stimulates in turn the production of both C-reactive protein and matrix metalloproteinase through its interaction with RAGE, thus contributing to the progression and vulnerability of the atherosclerotic plaque [58]. An intimate interplay between smooth muscle cells and HMGB1 has been described. On the first hand, smooth muscle cells actively secrete HMGB1 after cholesterol loading. On the other hand, SMCs proliferate, migrate, produce soluble phospholipase A2 and secrete more HMGB1 when exposed to HMGB1 [45,59].