Figure 3.

Stressed adipocytes in obese adipose tissue recruit neutrophils, which then further promote inflammation. Adipocytes produce adipokines such as leptin and cytokines such as interleukin-8 (IL-8). IL-8 is a potent chemoattractant for neutrophils. Once in the adipose tissue, neutrophils can recruit more blood neutrophils by releasing C–X–C motif chemokine ligand 2 (CXCL2), another important neutrophil chemoattractant. Neutrophils directly interact with adipocytes via the binding of integrin α_Mβ2 on the neutrophil to intercellular adhesion molecule 1 (ICAM-1) on the adipocyte. This interaction activates neutrophils and induces them to produce interleukin 1 beta (IL-1β) via the nuclear factor kappa B (NF-κB) and inflammasome (NLRP3) pathways. IL-1β is an important activator of macrophages. Neutrophils also produce tumor necrosis factor alpha (TNF-α), which further stimulates macrophages. Leptin, through its receptor, also activates the NF-κB pathway, resulting in the inhibition of neutrophil apoptosis. Free fatty acids (FFA) derived from adipocyte lipolysis can also attract neutrophils and stimulate them to produce more IL-1β. Neutrophils also produce elastase (NE) which impairs energy expenditure in the adipose tissue and directly activates macrophages. Granule protein cathelicidin (LL-37) can also activate the release of more proinflammatory cytokines from macrophages. Activated neutrophils can also recruit monocytes through the release of azurocidin, LL-37, cathepsin G, proteinase 3 (PR3), and human neutrophil peptides 1–3 (HNP1–3). In addition, lactoferrin, azurocidin, and HNP1–3 can induce polarization of macrophages towards the M1 proinflammatory phenotype.