Characterisation of HMGB1 in inflammation

High mobility group box chromosomal protein 1 (HMGB1) was discovered over three decades ago as a nuclear protein which is present in all mammalian nucleated cells. Subsequent studies have revealed additional properties of HMGB1 besides its originally described nuclear functions. Extracellular HMGB1 induces cellular migration, recruits stem cells, possesses antibacterial functions and somewhat surprisingly is involved in proinflammatory responses. HMGB1 can be released from certain cells in two distinct ways, either passively by dying cells or through active release from multiple cell types such as myeloid cells. The active secretion of HMGB1 is mediated via a non-classical pathway involving secretory lysosomes, a route sharing many features with the IL-1β secretion pathway.

My studies of macrophages from RAGE gene-deficient mice indicate that RAGE is the major functional receptor for HMGB1 on these cells. The results also show that HMGB1 interacts with additional receptor(s), since the absence of RAGE molecules did not completely abolish HMGB1-induced cytokine production. HMGB1 needed to form complexes with selected endogenous and exogenous danger signals in order to promote inflammation, as highly purified HMGB1 on its own did not induce cytokine production.

I have demonstrated the potential involvement of HMGB1 in the pathogenesis of a novel spontaneous experimental arthritis model, DNase II x Interferon type I receptor double gene-deficient mice. Marked, aberrant cytoplasmic and extracellular HMGB1 expression was evident in joint tissues from arthritic mice. HMGB1 and anti-HMGB1 antibodies could be detected in serum long before established disease, suggesting a role for HMGB1 in the initiation phase of the disease.

Finally, I have used a novel approach to inhibit extracellular HMGB1 release by inducing its nuclear retention. Chromatin sequestration of HMGB1 by oxaliplatin ameliorated collagen-induced arthritis in mice. Nuclear retention of HMGB1 was also demonstrated to be a potential mechanism for the therapeutic effects of gold salts which are commonly used in rheumatic diseases.

In conclusion, these studies demonstrate that HMGB1 when complexed with distinct molecules potentiates inflammation, provide further evidence of a role of extracellular HMGB1 in inflammatory arthritis, and that targeting HMGB1 is therapeutically beneficial.

List of scientific papers

I. Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, Nawroth P, Andersson U, Harris RA, Harris HE (2005). "RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages." Scand J Immunol 61(1): 1-9
https://pubmed.ncbi.nlm.nih.gov/15644117

II. Hreggvidsdottir HS, Östberg T, Wähämaa H, Schierbeck H, Aveberger AC, Klvenvall L, Palmblad K, Ottosson L, Andersson U, Erlandsson Harris H (2008). "The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation." (Submitted)

III. Östberg T, Nagata S, Kawane K, Yang H, Chavan S, Klevenvall L, Aveberger AC, Andersson U, Erlandsson Harris H, Palmblad K (2008). "HMGB1 participates in the pathogenesis of a novel experimental arthritis model that recapitulates rheumatoid arthritis" (Submitted)

IV. Ostberg T, Wähämaa H, Palmblad K, Ito N, Stridh P, Shoshan M, Lotze MT, Harris HE, Andersson U (2008). "Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis." Arthritis Res Ther 10(1): R1. Epub 2008 Jan 7
https://pubmed.ncbi.nlm.nih.gov/18179697

V. Zetterström CK, Jiang W, Wähämaa H, Ostberg T, Aveberger AC, Schierbeck H, Lotze MT, Andersson U, Pisetsky DS, Erlandsson Harris H (2008). "Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate." J Leukoc Biol 83(1): 31-8. Epub 2007 Oct 3
https://pubmed.ncbi.nlm.nih.gov/17913975