Skip main navigation
Poster Abstract Presentations
Poster Session I

Abstract 162: Exposure of Human Macrophages to Tobacco Smoke Induces Hmgb1 Release on Microvesicles That Cause Monocyte Recruitment and Impairment of Insulin Signaling in Adipocytes

Originally published, Thrombosis, and Vascular Biology. 2013;33:A162


    Smokers show increased prevalence of insulin resistance and type 2 diabetes. The underlying mechanisms, however, remain poorly understood. We recently implicated a role for HMGB1, a damage-associated molecular pattern previously shown to be released as a soluble molecule. We reported that exposure of human macrophages to tobacco smoke extract (TSE) provokes the release of HMGB1 in two forms: as a soluble molecule and on membrane microvesicles (MV). The HMGB1 on TSE-induced MVs mediates crucial crosstalk with adipocytes, e.g., these particles stimulate MCP1 secretion by adipocytes and the recruitment of monocytes.


    To explore the mechanisms by which HMGB1 is released on MVs, and the harmful effects of the TSE-MVs on macrophage-adipocyte crosstalk.


    To examine how HMGB1 is released on MVs, we found that exposure of human macrophages to TSE upregulated HMGB1 expression, induced its gradually translocation from the nucleus to the cytosol and plasma membrane, in a time-dependent manner, and then the release of HMGB1 both as a soluble molecule and on TSE-MVs. Inhibition of the nuclear protein exporter, chromosome region maintenance 1 (CRM1), by using CRM1 inhibitor III, attenuated the translocation of HMGB1 from the nucleus and its export on microvesicles. To examine biological effects, we found that treatment of adipocytes with TSE-MVs inhibited insulin-induced phosphorylation of IRS1 (Y612) and Akt (S473). Co-incubation of adipocytes with TSE-MVs and human monocytes produced more severe inhibition of insulin signaling than either TSE-MVs or monocytes did alone. Most importantly, pretreatment of macrophages with CRM1 inhibitor III, before exposure to TSE, attenuated the ability of TSE-MVs released by these cells to impair insulin-induced phosphorylation of Akt (S473) in adipocytes.


    Our results indicate that exposure of human macrophages to smoke upregulates HMGB1 expression and causes its release on microvesicles, which mediate harmful crosstalk from macrophages to adipocytes, causing the MCP1 secretion by adipocytes, further recruitment of monocyte/macrophages, and impairments in insulin signaling that may contribute to insulin resistance and the development of T2DM in tobacco smoke exposure.