Heme Induces IL-1β Secretion Through Activating NLRP3 in Kidney Inflammation

Abstract

To produce proinflammatory master cytokine IL-1β in macrophages, two stimulation pathways are needed including TLRs-NF-κB axis and NLRPs/ASC-caspase-1 axis. Different signals including exogenous and endogenous trigger inflammatory response distinctly. Among them, the role of endogenous stimulators of inflammation is poorly understood. As a component of hemoglobin, free heme is released when hemolysis or extensive cell damage occur which results in inflammatory response. Here, we find that heme induces IL-1β secretion through activating NLRP3 inflammasome in macrophages. Heme activates NLRP3 through P2X receptors, especially the P2X7R and P2X4R. Most importantly, significantly enhancement of heme level and activation of NLRPs/ASC-caspase-1 axis were observed in mice kidney after unilateral ureteral obstruction which could be inhibited by enforced expression of heme oxygenase-1 (HO-1). Our study proves that heme is a potential danger activator of NLRP3 inflammasome that plays an essential role in IL-1β secretion during kidney inflammation and provides new insight into the mechanism of innate immune initiation. Further investigation will be beneficial to develop new molecular target and molecular diagnosis indicator in therapy of kidney inflammation.

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

“…Exposure to myoglobin led to overexpression of the inflammasome component (Nlrp3) and proinflammatory factors (Il1b). This is consistent with (1) a recently published study showing that heme (a component of myoglobin) plays an essential role in Il1b secretion by macrophages during kidney inflammation 34 and (2) our data showing that macrophages exhibited high levels of Nlrp3 (in vitro and in vivo for R2-Gly) and also expressed P2rx7 (Supplemental Figure 5C). It was previously shown that myoglobin, through NO scavenging, reduced the immunosuppressive activity of IFN-g-activated macrophages.…”

Hemolysis-induced lethality involves inflammasome activation by heme

“…Moreover, hemeinduced inflammasome activation in the presence of serum was independent of macrophage death, ATP release, and functional P2X7 receptor. In the absence of serum, thioglycollate-elicited peritoneal macrophages stimulated with heme processed IL-1β and this involved required P2X receptor (63). We observed that in the absence of serum, inflammasome activation correlated with macrophage cell death determined by LDH release.…”

“…In a model of unilateral uretral obstruction, heme and the active forms of caspase-1 and IL-1β are increased (63). It has been demonstrated that inflammation, renal dysfunction, and death triggered by transient renal artery occlusion, a model of tubular necrosis induced by ischemiareperfusion, was dependent on NLRP3 (53), and intracerebral hemorrhage also activates the NLRP3 inflammasome in a mechanism dependent on mtROS (65).…”

“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels

“…Intracellular free heme can also induce signaling via nuclear receptors Rev-Erbα and Rev-Erbß [29, 132, 187]. Furthermore, the inflammasome activation via cryopyrin (AKA NLRP3) is sensitive to surplus intracellular heme while extracellular free heme can activate Toll-like receptor 4 (TLR4), supporting the idea that free heme is an endogenous danger signal [60, 65, 66, 131]. Given its inherent potential toxicity, the majority of free intracellular heme is promptly degraded by Hmox.…”