Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression

Abstract

High levels of plasma adiponectin are associated with low levels of inflammatory markers and cardioprotection. The mechanism via which adiponectin exerts its anti-inflammatory effect is yet unknown. In the present study, we demonstrate that globular adiponectin (gAd) induces the expression of the inactive isoform of IL-1R-associated kinases (IRAK), IRAK-M. Homologous deletion of IRAK-M in IRAK-M−/− mice abolished the tolerogenic properties of gAd because pretreatment of IRAK-M−/− macrophages with gAd did not suppress LPS-induced proinflammatory cytokine production. GAd activated the MAPKs MEK1/2 and ERK1/2 in macrophages via their upstream regulator Tpl2. Activation of ERK1/2 via Tpl2 appeared necessary for the induction of IRAK-M because gAd did not induce IRAK-M in Tpl2−/− macrophages or in macrophages pretreated with the MEK1/2 inhibitor UO126. In addition, activation of PI3K and Akt1 also appeared necessary for the induction of IRAK-M by gAd, because treatment of Akt1−/− macrophages or pretreatment of macrophages with the PI3K inhibitor wortmannin abolished gAd-induced IRAK-M expression. Analysis of IRAK-M expression in human peripheral blood cells confirmed that serum adiponectin was negatively associated with IRAK-M and responsiveness to LPS. In conclusion, our data demonstrate that IRAK-M is a major mediator of gAd-induced endotoxin tolerance in primary macrophages, expression of which depends on the activation of Tpl2/ERK and PI3K/Akt1 signaling pathways.

A New IRAK-M-Mediated Mechanism Implicated in the Anti-Inflammatory Effect of Nicotine via α7 Nicotinic Receptors in Human Macrophages

“…In fact, no significant differences in relation to the threshold concentration of nicotine or its time-course for stimulating IRAK-M expression were found between macrophages from either species. Furthermore, the time-course of the nicotine effect on protein expression in the two types of macrophage (Figure 1D) is very similar to that obtained in murine macrophages using adiponectin or LPS as stimuli [54]. Taken together, the above results indicate that induction of IRAK-M by nicotine is a reproducible and generalized process in macrophages, regardless of the species tested.…”

Molecular Mechanism Responsible for the Priming of Macrophage Activation

“…IRAK-M was shown to inhibit IRAK-1 function (21). PI3K pathway was shown to increase IRAK-M and down-regulate both the levels and activities of IRAK-1 (22,23,26,31). Furthermore, PI3K also induces RelB (49).…”

“…For example, IB␣ suppresses p65/RelA by secluding it in the cytoplasm; MAPK phosphatase 1 suppresses the activities of MAP kinases (20); IRAK-M suppresses interleukin receptor-associated kinase 1 (IRAK-1) (21); and RelB blocks the transcription of proinflammatory mediators by assembling a suppressive complex on their promoters (19). In addition, LPS is known to activate the phosphoinositide 3-kinase (PI3K) pathway, which dampens the expression of proinflammatory mediators through inducing negative regulators, including MAPK phosphatase 1, IRAK-M, and suppressing IRAK-1 (22)(23)(24)(25)(26). As a consequence, LPS (Ͼ1 ng/ml) causes a robust yet transient expression of proinflammatory media-tors, followed by a refractory tolerant state.…”

Immune Regulation in Obesity-Associated Adipose Inflammation

“…Because chronic low levels of LPS do not induce endotoxin tolerance in macrophages (43), a high-fat, high-carbohydrate diet could result in chronic innate immune-driven inflammation. Moreover, obesity reduces adiponectin levels (44), and because adiponectin can promote endotoxin tolerance (45), obesity may exacerbate the endotoxinmediated effect by removing a potentially protective factor. Interestingly, a major source of PAMPs in obesity may be the intestinal microbiota: in mice, a HFD induces adherence and translocation of commensal bacteria from the intestine into the blood and AT, correlating with an increase in inflammatory cytokines (46).…”