Ablation of Neuropilin 1 in Myeloid Cells Exacerbates High-Fat Diet–Induced Insulin Resistance Through Nlrp3 Inflammasome In Vivo

Abstract

Neuropilin 1 (Nrp1), a coreceptor for class 3 semaphorins and growth factors, is highly expressed in vascular cells and myeloid cells, including macrophages. Unlike well-characterized proangiogenic functions of endothelial cell Nrp1, the contributions of macrophage Nrp1 within the context of metabolic dysfunction remain to be established. The aim of this study was to determine the contributions of macrophage Nrp1 in high-fat diet (HFD)-instigated insulin resistance in vivo. Insulin sensitivity and Nlrp3 inflammasome activation were monitored in wild-type (WT) and myeloid cell-specific Nrp1 knockout (Nrp1myel-KO) mice fed an HFD (60% kcal) for 16 weeks. HFD-fed mice exhibited insulin resistance with reduced levels of Nrp1 in macrophages compared with chow-fed mice. Further, HFD-fed Nrp1myel-KO mice displayed accentuated insulin resistance, enhanced systemic inflammation, and dramatically increased Nlrp3 inflammasome priming and activation. Importantly, knockout of Nlrp3 ablated HFD-induced insulin resistance and inflammation in Nrp1myel-KO mice, indicating that Nrp1 reduction in macrophages instigates insulin resistance by increasing macrophage Nlrp3 inflammasome activation. Mechanistically, Nrp1 deletion activates the nuclear factor-κB pathway, which in turn accentuates the priming of Nlrp3, promotes Nlrp3-ASC inflammasome assembly, and results in the activation of Nlrp3. We conclude that the HFD-instigated Nrp1 reduction in macrophages exacerbates insulin resistance by promoting Nlrp3 inflammasome priming and activation.

An update on immune dysregulation in obesity‐related insulin resistance

“…A subset of neuropilin‐1 (NRP1) expressing ATMs has recently been found to protect against obesity . Myeloid cell‐specific Nrp1 deficiency (Nrp1 myel−KO mice) activates the NLRP3 inflammasome, which increases the synthesis of inflammatory IL‐1β and IL‐18 cytokines in macrophages . Additionally, inflammasome activation and subsequent IR do not occur in the AT of HFD‐fed Nlrp3 −/− mice that indicate the importance of the pathway in the induction of IR .…”

“…92 Myeloid cell-specific Nrp1 deficiency (Nrp1 myel−KO mice) activates the NLRP3 inflammasome, which increases the synthesis of inflammatory IL-1β and IL-18 cytokines in macrophages. 93,94 Additionally, inflammasome activation and subsequent IR do not occur in the AT of HFD-fed Nlrp3 −/− mice that indicate the importance of the pathway in the induction of IR. 93 After HFD in mice, Th1 cytokines (IFN-γ, TNF-ɑ and granulocytemacrophage colony-stimulating factor [GM-CSF]) induce the generation of classically activated pro-inflammatory CD11c + M1-like macrophages within the AT that contributes to the induction of IR.…”

Myeloid cell neuropilin 1 ameliorates high-fat diet-induced insulin resistance via suppression of Nlrp3 inflammasome

“…With respect to how Nrp1 ablation exacerbates insulin resistance in vivo, a number of important findings are noteworthy. Firstly, we observed that systemic inflammation significantly increased in HFD-fed Nrp1 myel-KO mice [6] . Secondly, Nrp1 myel-KO mice displayed aberrant activation of Nlrp3 inflammasome, as evidenced by elevated levels of Nlrp3, cleaved caspase 1 p20, pro-IL-1β, IL-1β p17, or IL-18 [6] .…”

“…In our recently published article, we provided first evidence of a direct link between Nrp1 and obesity. HFD-fed obese mice exhibited decreased Nrp1 expression in macrophages rather than other detected cells [6] . In addition, by generating myeloid cell-specific Nrp1 deficient (Nrp1 myel-KO ) mice, we demonstrated that Nrp1 deficiency exacerbated insulin resistance upon HFD relative to wild-type, control mice group [6] .…”

“…HFD-fed obese mice exhibited decreased Nrp1 expression in macrophages rather than other detected cells [6] . In addition, by generating myeloid cell-specific Nrp1 deficient (Nrp1 myel-KO ) mice, we demonstrated that Nrp1 deficiency exacerbated insulin resistance upon HFD relative to wild-type, control mice group [6] . Collectively, these data indicate that macrophage Nrp1 negatively regulates obesity-induced insulin resistance.…”