Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes1, 2. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process3, 4, 5, 6, 7, 8. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells9, 10, 11. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models12. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.
At a glance
- Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010). &
- Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011). &
- CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009). et al.
- Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009). et al.
- Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009). et al.
- B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011). et al.
- Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 15, 940–945 (2009). et al.
- Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011). et al.
- Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011). , , &
- Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173–182 (2006).
- Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).
- Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6, 541–550 (2006).
- Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49, 1894–1903 (2008). , , &
- The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase–—GW311616A a development candidate. Bioorg. Med. Chem. Lett. 11, 895–898 (2001). et al.
- Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am. J. Pathol. 175, 1473–1482 (2009). et al.
- Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 16, 219–223 (2010). et al.
- The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 9, 1732–1737 (2010).
- Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J. Biol. Chem. 276, 35494–35499 (2001). et al.
- Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett. 544, 129–132 (2003). et al.
- Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999). et al.
- GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010). et al.
- Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat. Med. 17, 618–622 (2011). et al.
- Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J. Biol. Chem. 285, 15333–15345 (2010). et al.
- The mechanism mediating the activation of acetyl–coenzyme A carboxylaseα gene transcription by the liver X receptor agonist T0-901317. J. Lipid Res. 47, 2451–2461 (2006). &
- Structural characterization of mouse neutrophil serine proteases and identification of their substrate specificities: relevance to mouse models of human inflammatory diseases. J. Biol. Chem. 284, 34084–34091 (2009). et al.
- Supplementary Text and Figures (950K)
Supplementary Figures 1–7