Heme oxygenase-1/carbon monoxide as modulators of autophagy and inflammation

Abstract

Heme oxygenase-1 (HO-1) catalyzes heme degradation to generate biliverdin-IXα, carbon monoxide (CO), and iron. The HO-1/CO system confers cytoprotection in animal models of organ injury and disease, via modulation of inflammation and apoptosis. Recent studies have uncovered novel anti-inflammatory targets of HO-1/CO including regulation of the autophagy and inflammasome pathways. Autophagy is a lysosome-dependent program for the turnover of cellular organelles such as mitochondria, proteins, and pathogens; which may downregulate inflammatory processes. Therapeutic modulation of autophagy by CO has been demonstrated in models of sepsis. The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome regulates the maturation of pro-inflammatory cytokines. CO can regulate NLRP3 inflammasome activation and associated pro-inflammatory cytokines production and promote the resolution of inflammation by upregulating the synthesis of specialized pro-resolving mediators (SPMs). Mitochondria may represent a proximal target of HO-1/CO action. HO-1 may localize to mitochondria in response to stress, while CO can moderate mitochondrial dysfunction and regulate mitochondrial autophagy (mitophagy) and biogenesis. The interplay between mitochondrial autophagy, mitochondrial dysfunction, and the regulation and resolution of inflammation may make important contributions to the protection afforded by HO-1/CO in cellular and organ injury models. Recent studies have continued to explore the potential of CO for clinical applications.

Keywords: Autophagy; Carbon monoxide; Heme Oxygenase-1; Inflammasome; Inflammation; Mitophagy.