CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies

Abstract

BackgroundAdipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L – an established marker and mediator of cardiovascular disease – induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo.Methodology/Principal FindingsWT or CD40L−/− mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L−/− mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L−/− mice. However, CD40L−/− mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L−/− mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels.ConclusionWe present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease.

CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance

“…Ϫ/Ϫ mice indicated that CD40L deficiency attenuates HFD-induced adipose tissue inflammation (32,46), which is opposite to what we observed here in CD40 Ϫ/Ϫ mice. However, since CD40L can signal through a non-CD40 pathway (51), differences between CD40…”

“…CD40 Ϫ/Ϫ mice develop hepatic steatosis and increased de novo lipogenesis in the liver. Recent literature has implicated CD40L as a protective factor against hepatic steatosis (43,46), which has a strong association with insulin resistance (29). Since we found impaired systemic insulin sensitivity in CD40…”

“…In fact, the CD40-CD40L axis has recently been implicated in the pathogenic complications of obesity (32,43,46). However, various research groups have reported conflicting roles of CD40L in diet-induced obesity in mice.…”

“…However, various research groups have reported conflicting roles of CD40L in diet-induced obesity in mice. For example, two studies showed that CD40L deficiency aggravated hepatic steatosis in obesity (43,46) whereas an-other study indicated that the absence of CD40L attenuated diet-induced steatosis (32). Furthermore, in one study, CD40L deficiency improved insulin resistance (32), whereas in another study lack of CD40L in mice did not ameliorate high-fat diet-induced insulin resistance (46).…”

“…For example, two studies showed that CD40L deficiency aggravated hepatic steatosis in obesity (43,46) whereas an-other study indicated that the absence of CD40L attenuated diet-induced steatosis (32). Furthermore, in one study, CD40L deficiency improved insulin resistance (32), whereas in another study lack of CD40L in mice did not ameliorate high-fat diet-induced insulin resistance (46). A caveat in these studies is that CD40L can mediate inflammation through a CD40-independent mechanism by interacting directly with Mac-1/CD11b, which is expressed abundantly on macrophages and monocytes (51).…”