Impaired wound healing in type 1 diabetes is dependent on 5-lipoxygenase products

Abstract

Type 1 diabetes is associated with systemic low grade inflammation (LGI). We have previously shown that LGI in diabetic mice depends on systemic circulation of leukotriene (LTB4) which potentiates the toll-like/IL1β receptors response in macrophages. Impaired wound healing is an important co-morbidity in diabetes, and macrophages play a key role in this process. Here, we investigated the role of leukotrienes on monocytes and macrophages phenotype and in the impaired wound healing in diabetic mice. Type 1 diabetes was induced with streptozotocin in 129SvE wild-type (WT) and leukotrienes-deficient 5LO−/− (5-lipoxygenase knockout) mice. In diabetics, the systemic levels of LTB4, TNF-α, IL-6, IL-10, IL-12 and IFNγ were increased as well as the frequency of pro-inflammatory monocytes (CD11b+Ly6ChighLy6G−) compared to healthy mice. In diabetic 5LO−/− mice, these parameters were similar to those in healthy mice. Resident peritoneal macrophages from diabetic WT mice showed a classically activated M1-like phenotype (high Nos2, Stat and Il12 expression, and nitrite levels). Macrophages from diabetic 5LO−/− mice presented alternatively activated M2-macrophages markers (high Arg1 and Chi3l3 expression and arginase activity) and when stimulated with IL4, enhanced phosphorylated-STAT6. Cutaneous wound healing in diabetic WT mice was impaired, which correlated with the decreased frequency of M2-macrophages (CD45+F4/80+CD206+) in the lesions. In diabetic 5LO−/− mice, the frequency of M2-macrophages in the wound was similar to that in healthy mice, suggesting that the impaired healing of diabetic mice depends on 5LO products. The inhibition of leukotrienes or antagonism of its receptors could be a therapeutic alternative for diabetic patients with impaired healing.

Leukotriene-B4 modulates macrophage metabolism and fat loss in type 1 diabetic mice

“…Noteworthy, a similar lipid buffering function was also seen in adipose tissue resident macrophages in conditions of excessive fatty acid release by adipocytes. This resulted in their polarization to M1 and M2 profile as it did in peritoneal macrophages of T1D mice . These findings reveal the complexity and heterogeneity of response of different macrophage populations to excessive amounts of lipids.…”

“…In T1D, high LTB4 levels trigger systemic inflammation and affect macrophages phenotype . Also, it is known that inflammatory program in macrophages is directly related to altered lipid metabolism in these cells .…”

“…Evidence gathered over the years indicates that monocytes and macrophages play a central role in the development and maintenance of the chronic low‐grade inflammation commonly found in metabolic diseases including T1D . Monocytes/macrophages are very plastic cells that differentiate into heterogeneous subpopulations and display distinct functions depending on microenvironment stimuli.…”

“…High systemic levels of LTB4 are also found in T1D mice. In this condition, LTB4 was shown to enhance inflammation, proinflammatory macrophage polarization, and signaling to the canonical TLR/IL‐1 receptor family …”

“…In this condition, LTB4 was shown to enhance inflammation, proinflammatory macrophage polarization, and signaling to the canonical TLR/IL-1 receptor family. 6,7,15,18 In the present study, we investigated the effects of pharmacologic inhibition of LTB4/BLT1 on body composition, adiposity, dyslipidemia, and macrophage metabolism in an experimental mouse model of streptozotocin (STZ)-induced T1D. We mainly found that LTB4 via BLT1 receptor is involved in systemic metabolic changes as well as in macrophage metabolism.…”