Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

Obese adipose tissue promotes monocytosis via macrophage activation of the NLRP3-inflammasome and IL-1β (#135)

Andrew J Murphy 1 , Prabhakara R Nagareddy 2 , Ira J Goldberg 3
  1. Baker IDI Heart and Diabetes Institute, St Kilda Road Central, VIC, Australia
  2. University of Kentucky, Lexington, USA
  3. Columbia University, New York, USA

Metabolic syndrome and type 2 diabetes increase the risk of developing cardiovascular disease (CVD), a condition associated with leukocytosis. However, the mechanisms that promote leukocytosis in these conditions remain poorly understood. Using mouse models of obesity we found that increased numbers of circulating monocytes and neutrophils was due to enhanced proliferation of myeloid progenitor cells in the bone marrow (BM). We confirmed, via adipose tissue transplantation and weight loss studies, that enhanced myelopoiesis was due to signals originating from the adipose tissue. S100A8/A9 is produced in obese visceral adipose tissue (VAT) and activates TLR4-MyD88 (but not TRIF/TRAM) in adipose tissue macrophages (ATMs) to simulate IL-1β production. This was confirmed using cell specific knockouts of MyD88 and hematopoietic deletion of the IL-1 receptor (IL-1R). We discovered a significant upregulation of the IL-1R on myeloid progenitor cells in the BM of obese mice and found that IL-1β could directly promote GMP proliferation in an IL-1R dependent manner. Deletion Nlrp3 also abolished obesity-induced monocytosis, indicating a key role for inflammasone activation. Together these results show that obese VAT stimulates BM progenitor cell proliferation to over-produce monocytes and neutrophils.