Nucleotides released from palmitate-activated murine macrophages attract neutrophils

Abstract

Obesity and elevation of circulating free fatty acids are associated with an accumulation and proinflammatory polarization of macrophages within metabolically active tissues, such as adipose tissue, muscle, liver, and pancreas. Beyond macrophages, neutrophils also accumulate in adipose and muscle tissues during high-fat diets and contribute to a state of local inflammation and insulin resistance. However, the mechanisms by which neutrophils are recruited to these tissues are largely unknown. Here we used a cell culture system as proof of concept to show that, upon exposure to a saturated fatty acid, palmitate, macrophages release nucleotides that attract neutrophils. Moreover, we found that palmitate up-regulates pannexin-1 channels in macrophages that mediate the attraction of neutrophils, shown previously to allow transfer of nucleotides across membranes. These findings suggest that proinflammatory macrophages release nucleotides through pannexin-1, a process that may facilitate neutrophil recruitment into metabolic tissues during obesity.

The Role of Connexin 43 and Pannexin 1 During Acute Inflammation

“…Moreover, the authors found that palmitate upregulated Panx1-channel expression in macrophages mediating neutrophil attraction by release of nucleotides such as ATP. The thereby following purinergic receptor stimulation and signaling induces neutrophil migration (Tam et al, 2020). These results emphasize the role of Panx1 in neutrophil recruitment and its contribution to inflammatory response during obesity.…”

“…Recently, Tam et al (2020) demonstrated that during metabolic inflammation pro-inflammatory macrophages release chemotactic factors upon exposure to saturated fatty acids, such as palmitate, which was associated with recruitment and infiltration of neutrophils into adipose tissues. Heat inactivation or proteinase K digestion of media released by fatty acid treated macrophages did not alter neutrophil recruitment but was effective to inhibit CXCL-1 induced chemotaxis suggesting that these macrophage derived chemotactic factors are not proteins (Tam et al, 2020). Moreover, the authors found that palmitate upregulated Panx1-channel expression in macrophages mediating neutrophil attraction by release of nucleotides such as ATP.…”

<p>Characterization and Treatment of Inflammation and Insulin Resistance in Obese Adipose Tissue</p>

“…This may promote the recruitment of neutrophils into obese AT. 50 These results indicate that in diet-induced obesity, neutrophils quickly infiltrate the abdominal AT and cause chronic inflammation.…”

Chronic tissue inflammation and metabolic disease

“…In obese adipose tissue, decreased ILC2 cells are associated with decreased local eosinophil numbers. Finally, the recruitment of neutrophils into adipose tissue increases in obesity, and factors released from neutrophil granules, such as neutrophil elastase and myeloperoxidase, can contribute to the development of insulin resistance (Talukdar et al 2012;Tam et al 2020).…”