Potentiated macrophage activation by acid sensing under low adiponectin levels

Abstract

Adiponectin can protect against inflammation; one of the mechanisms involves direct, inhibition of macrophages (MΦ). We postulated that adiponectin anti-sense transgenic (AsTg) mice raised in our laboratory are prone to inflammation because of systemic low adiponectin levels. The writhing response to acetic acid was utilized as an in vivo inflammatory model, and using Ca(2)(+), response to the acid was exploited in vitro to evaluate the function of resident peritoneal MΦ. The in vivo response to the acid was increased and the Ca(2)(+) response of MΦ was enhanced in AsTg mice, compared with those in wild type (WT) mice. In parallel with these enhanced responses, MΦ from AsTg mice augmented TNF-α and IL-6 mRNA expression. We further analyzed the enhancement in activity of MΦ from AsTg mice by acid sensing using specific inhibitors, amiloride for acid-sensing ion channels (ASICs) and KB-R7943 for Na(+)/Ca(2)(+) exchangers (NCXs). Our results indicated that in AsTg mice, the Ca(2)(+) response to the acid was facilitated in MΦ by a low threshold of ASIC1 and NCX1 molecules and the activity of these channel was possibly regulated by adiponectin.

Keywords: ANOVA; ASICs; Acid-sensing ion channels; Adiponectin; Adiponectin anti-sense transgenic mice; AsTg; CAMKs; CLP; CREB; ER; FBS; HBSS; HEPES-buffered saline; Inflammation; LPS; Macrophages; MΦ; NCXs; Na(+)/Ca(2)(+) exchangers; Na(+)/Ca(2+) exchangers; TRPC3; TRPM2; TRPV1; TRPV2; Tg; WAT; [Ca(2)(+)](i); acid-sensing ion channels; adiponectin anti-sense transgenic; analysis of variance; cAMP response element-binding protein; calcium/calmodulin-dependent protein kinases; cecal ligation and puncture; endoplasmic reticulum; fetal bovine serum; intracellular Ca(2)(+) concentration; lipopolysaccharide; macrophage; thapsigargin; transient receptor potential cation channel, subfamily M, member 2; transient receptor potential cation channel, subfamily V, member 1; transient receptor potential cation channel, subfamily V, member 2; transient　receptor potential cation channel, subfamily C, member 3; white adipose tissue.