GMP proliferation and differentiation in diabetes are regulated by the sympathetic nervous system  |  Diabetes increases sympathetic tone and tyrosine hydroxylase (TH)+ splenic leukocytes. TH is a rate limiting enzyme in catecholamine synthesis. The catecholamines bind to the β2 adrenergic receptor on splenic GMP. This leads to the proliferation and differentiation of splenic GMP, resulting in exaggerated myeloid cell production. Newly made splenic myeloid cells are recruited to atherosclerotic plaques. These myeloid cells make the plaques vulnerable to rupture.

There is a growing body of research on the neural control of immunity and inflammation. However, it is not known if the nervous system can regulate the production of inflammatory myeloid cells from hematopoietic progenitor cells in disease conditions. We found that inflammatory myeloid cell numbers in diabetic patients were strongly correlated with plasma norepinephrine levels, suggesting the role of sympathetic activation in myeloid cell production. Diabetic mice had increased number and proliferation of splenic granulocyte macrophage progenitors (GMP), the immediate precursors of myeloid cells. Additionally, the spleens of diabetic mice and patients contained higher number of tyrosine hydroxylase (TH)-expressing leukocytes that produced supranormal levels of catecholamines. Surgical and pharmacological splenic sympathetic denervation in diabetic mice diminished proliferation and differentiation of splenic GMP, resulting in decreased inflammatory myeloid cell numbers in the spleen. Furthermore, we observed that splenic GMP of mice and patients expressed the b₂ adrenergic receptor. Selective b₂ blocker treatment and genetic deficiency in the b₂ adrenergic receptor in diabetic mice significantly reduced splenic GMP proliferation and myeloid cell generation. Finally, mice lacking TH-producing leukocytes had significantly reduced GMP proliferation and differentiation, resulting in diminished myelopoiesis. Taken together, our study demonstrates that catecholamines produced by leukocytes and sympathetic nerve termini play an unexpected role in GMP proliferation and myeloid cell generation.