Age-related decline in HMGB1-neutralizing IgM autoantibody response impairs resistance to high-fat diet in mice

As we age, it becomes increasingly important to reduce the consumption of fatty foods. In mice, we also find that after consuming a high-fat diet, older mice develop insulin resistance more easily than young mice. But how aging renders both humans and mice more vulnerable to the detrimental effect of fatty foods is not completely known. Fatty food consumption has been shown to increase extracellular HMGB1, a key player in driving sterile inflammation. In this study, we show in mice that aging impairs the ability to produce, after stimulation of HMGB1, a neutralizing anti-HMGB1 IgM autoantibody that controls the extracellular HMGB1 level. This impairment in eliciting the anti-HMGB1 IgM response renders mice, regardless of age, more susceptible to the development of insulin resistance after consuming high-fat diet. The cause of this impairment lies within the B-1 cells that produce the autoantibody. As they age within the mice, these B-1 cells become less sensitive to the HMGB feedback stimulation mediated via TLR4 signaling. As a result, the mice fail to upregulate the anti-HMGB1 IgM autoantibody in response to the increase in extracellular HMGB1 following fatty food consumption. These findings point to age-related decline in eliciting the anti-HMGB1 IgM response as one of the factors contributing to age-related loss of tolerance to fatty foods. The possibility to explore this immune axis as a therapeutic target emerges.