Figure 2.

S100A8/A9 drives myelopoiesis and monocytosis in diabetes and obesity. (A) Adipose tissue inflammation in obesity promotes monocytosis through S100A8/A9-TLR4 signaling on CD11c⁺ adipose tissue macrophages (signal 1, other potential mediators in gray) and activation of the NLRP3 inflammasome (signal 2) to promote IL-1β, which signals through the IL1R on common myeloid progenitors (CMPs) and granulocyte–macrophage progenitors (GMPs) to induce myelopoiesis. This results in both increased circulating monocytes and feeds back to increase CD11c⁺ macrophages. (B) Hyperglycemia promotes monocytosis by direct signaling of neutrophil-derived S100A8/A9 via RAGE on CMPs and macrophages in the bone marrow, promoting CMP and GMP proliferation and differentiation via autocrine and paracrine (M-CSF and GM-CSF) signaling, respectively. These monocytes infiltrate atherosclerotic lesions to promote atherogenesis (further detailed in Figure 1 ).