Age-related impairment in anti-HMGB1 IgM response potentiates type 2 diabetes

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PROJECT SUMMARY Type 2 diabetes (T2D) is a common disease in older adults and also a risk factor for other age-related diseases. A common link of these diseases is age-related increase in low-grade chronic inflammation (known as “inflammaging”). Chronic inflammation is triggered partly by damage-associated molecular patterns (DAMPs). HMGB1 (High-Mobility Group Box 1) is a prototypical DAMP that is evolutionarily conserved, and it is implicated in the pathogenesis of several age-related diseases including T2D and cardiovascular disease (CVD). Recently, in both normal mice and healthy human blood donors, we identified an endogenous anti- HMGB1 IgM antibody (Ab) that neutralizes the proinflammatory activity of HMGB1, via binding to a highly conserved epitope of HMGB1, namely HMW4. This anti-HMW4 IgM was upregulated in mice in response to challenge with high fat diet (HFD). Critically, the ability to upregulate anti-HMW4 IgM (upon HFD challenge) was impaired in middle-aged (9-month-old) male and older (14-month-old) female mice, which correlated with the increase in vulnerability (or decrease in tolerance) to the diabetogenic effect of HFD, as reflected by more rapid onset of insulin resistance (IR). These data compel us now to test our hypothesis that anti-HMW4 IgM plays a diabeto-protective role, and the age-related impairment in raising this IgM represents one of the factors contributing to the increase in vulnerability to the diabetogenic effect of HFD and, thus, the risk of IR/T2D. We propose two specific aims. Specific Aim #1 is to determine whether anti-HMW4 IgM is diabeto- protective. We will use two complementary approaches: 1) Determining whether infusion of anti-HMW4 IgM into young, middle-aged, and age mice (“gain-of-function”) confers protection against HFD-induced IR and inflammation. 2) Determining whether diminishing this IgM response by depletion of anti-HMW4 IgM-producing B-1 cells in young mice (“loss-of-function”) impairs their tolerance to HFD. Specific Aim #2 is to identify age- related defects in HMW4-reactive B-1 cells that impair the anti-HMW4 IgM response, with the focus on the TLR4 signaling axis. We will use two approaches: 1) Analyzing TLR4 activation in peritoneal HMW4-reactive B-1 cells from young, middle-aged, and aged mice to determine whether middle-aged and aged mice have a defect in TLR4 signaling. 2) Treating middle-aged and aged mice with the TLR4 agonist MPLA to determine whether enhanced TLR4 stimulation restores their anti-HMW4 IgM response and tolerance to HFD. The significance of our studies lies in a few aspects. The studies will identify an age-related mechanism for regulating chronic inflammation and the body’s tolerance to fatty foods. They will provide valuable insight into the immune-metabolic interplay in metabolic challenge. They are expected to yield a novel target for immunotherapy (i.e., anti-HMW4 IgM-producing B cells) and an “injectable” therapeutic (i.e., anti- HMW4 IgM) for age-related diseases including T2D and CVD.