Since COVID-19 is a global health emergency, any hypothesis that can explain the course
and complications of this disease, and lead to a more focused treatment and self-limiting
progression of the infection, should be put forward. A whole series of symptoms and
features related to this disease have emerged from reports including fever, cough,
myalgia, sore throat, dyspnea, headache, lymphopenia, and acute respiratory distress
syndrome (ARDS), but also acute cardiac and kidney injury, secondary infection, shock
, vasculitis, thrombosis, and disseminated intravascular coagulation. In some patients,
significant levels of antiphospholipid antibodies have been found , which, in association
with extremely elevated proinflammatory cytokines, are probably responsible for the
worst course and outcome, and have led to the current ongoing trials on biological
drugs against IL-1 receptor, IL-6, and IL-6 receptor, among others . Fibrosis is
present in the lungs of severely affected patients . Amyloidosis and thrombosis
have been reported by colleagues as present in autoptic specimens but have not yet
been reported in the literature.
Patients with obesity are at an increased risk of developing COVID-19 [5, 6], possibly
aggravated further by the presence of nonalcoholic fatty liver disease . Obesity
is also characterized by low-grade chronic inflammation.
High mobility group box-1 (HMGB1) is a chromatin-linked, nonhistomic, small protein
with cytokine activity that has nuclear, cytosolic, and extracellular actions. It
binds to chromosomal DNA but also to Toll-like receptor 3 (TLR3), TLR4, and the receptor
for advanced glycation end products (RAGE) that activates nuclear factor (NF)-κB (Fig.
1a), which mediate the upregulation of leukocyte adhesion molecules as well as the
production of proinflammatory cytokines and angiogenic factors that promote inflammation.
HMGB1 was initially known as alarmin and is a well-recognized damage-associated molecular
pattern (DAMP) protein.
HMGB1 has been extensively studied within the field of endocrinology as it is clearly
involved with obesity , insulin resistance, and diabetes , and more recently
polycystic ovary disease , another condition characterized by low-grade chronic
inflammation (Fig. 1b).
Interestingly, it has been recognized that HMGB1 regulates autophagy  and could
potentially be a biomarker of acute lung injury . Autophagy is one of the mechanisms
involved in COVID-19 and is involved in viral entry and replication in cells, so targeting
this process has been suggested as a possible novel therapeutic strategy for COVID-19
Furthermore, HMGB1 expression is increased in thrombosis-related diseases [13, 14],
and has been studied in alveolar epithelial cells . Finally, HMGB1, via RAGE,
mediates sepsis-triggered amyloid-β accumulation in diseases of the central nervous
system associated with impaired cognitive function, e.g., neurodegenerative diseases
Most interestingly, HMGB1 gene polymorphisms are associated with hypertension in the
Han Chinese population , which also suggests that it could be implicated in the
outcome and course of COVID-19 in some individuals.
It is now well known that SARS-CoV2 requires angiotensin-converting enzyme (ACE) II
receptors for viral entry and replication . Kuba et al.  showed in mice that
SARS-CoV downregulated ACE II protein, contributing to severe lung injury. Interestingly,
ACE II overexpression has been reported to reduce HMGB1, besides reducing apoptosis
in the myocardium postinfarction, in a rat model . This leads to the hypothesis
that a reduction in ACE II induced by the virus would in turn increase HMGB1, thus
contributing to the “cytokine storm” and the worst scenarios seen with COVID-19 infection.
The inflammasome mediates HMGB1 translocation from the nucleus to the cytoplasm, with
subsequent release from the cell via type 1 interferon JAK/STAT1 activation. Thus,
pharmacological inhibition of JAK/STAT1 could be an approach for reducing circulating
HMGB1 . HMGB1 is recognized as a drug target, in particular for the salicylic
acid (SA) derivatives 3-aminoethyl SA and amorfrutin B1, and methotrexate, inflachromene,
and glycyrrhizin have also been shown to lower HMGB1 . In 2003, in an in vitro
model, a German group used glycyrrhizin to inhibit the replication of SARS-CoV1, the
virus that was circulating at that time, and described this compound as effective
as ribavirin and mycophenolic acid, and more effective than 6-azauridine and pyrazofurin.
This finding was confirmed in vitro using serum samples from patients, but the mechanism
of action remained unclear .
In addition to these considerations, in 2004, it was hypothesized that HMGB1 could
play a possible pathogenic role in SARS-Cov1 .
Finally, my research group previously showed that cystic fibrosis transductance regulator
(CFTR) malfunction, as found in cystic fibrosis, increases HMGB1 serum concentrations,
along with inflammation, and further increases are observed at the onset of the specifically
related diabetes . This suggests that changes in CFTR expression and/or specific
polymorphisms could play a role, particularly in the lung, and some of the new CFTR
modulators should be considered for treatment if this were indeed the case [25, 26].
Furthermore, diabetes is a recognized risk factor for Sars-CoV2 infection , and
HMGB1 is known to be increased in diabetes .
In conclusion, I support the need for assaying HMGB1 in the serum samples of COVID-19
patients who have been affected differently and are thus currently receiving different
treatment. This would clarify whether HMGB1 could be a marker of poor prognosis and
a potential target for treatment. Furthermore, could the HMGB1 gene polymorphisms
explain some of the variations observed in these patients? If so, this should be addressed
and integrated into treatment.
Should we now be considering add-on treatment with drugs like glycyrrhizin, that reduce
HMGB1, and then rapidly hypothesize the dose and mode of administration?
I declare there are no competing interests.