Editorial: Heme Oxygenases: Novel Regulators of Reproductive Processes

Heme oxygenase (HO) is a ubiquitous enzyme with various properties, but its main function is catalyzing the rate-limiting step in heme degradation to produce equimolar quantities of biliverdin, iron, and carbon monoxide (CO) (Tenhunen et al., 1968). Of its three isozymes, HO-2 and HO-3 are constitutively-expressed and HO-1 is inducible and acts as stress-response protein. It is not only cytoprotective (Vile et al. prevent tissue injury. Also, HO-1 is known to regulate innate and adaptive immunity, and therefore may prevent immune-mediated inflammatory diseases (Wagener et al. Pioneering work from the late Fritz Bach revealed the importance of HO-1 in organ transplantation. Using wild-type (WT, Hmox1 +/+) and Hmox1 −/− mice, Soares et al. (1998) demonstrated that the rapid expression of HO-1 by xenograft endothelial cells, smooth muscle cells, and cardiac myocytes protects xenografts from rejection. The role of HO-1 in xenograft and allograft acceptance is due to its cytoprotective properties that support cell survival and function within the transplanted organ. Moreover, HO-1 can reduce the graft immunogenicity by directly modulating recipient immune response such that regulatory responses are generated. The activation of HO-1 expression in the graft and in immune cells of the recipient can prevent rejection and promote immunotolerance, and probably due to the detoxification of free heme by HO-1 (Soares and Bach, 2007). Using a mouse model where tolerance is induced by donor-specific transfusion and anti-CD40L, Yamashita et al. (2006) observed that HO-1 is necessary for long-term graft tolerance as grafts do not survive in Hmox1 −/− compared to WT control recipients. Modulation of HO-1 was necessary to promote graft tolerance. Donor-specific transfusion alone failed to prolong survival of transplanted hearts, but long-term survival and tolerance were achieved after HO-1 induction. HO-1 induction plus donor-specific transfusion was associated with increases in regulatory T-cells (Tregs) (Yamashita et al., 2006). The immunomodulatory effect on cells from graft recipients is based on the fact that HO-1 directly modulates the phenotype of dendritic cells (DCs) (Moreau et al., 2009). HO-1 is constitutively expressed in immature DCs; however, its expression decreases during DC maturation. HO-1 upregulation can maintain DCs in an immature state, which suppresses the immune response, and then leads to antigen-specific Treg generation (George et al., 2008; Schumacher et al., 2012). Because Tregs from Hmox1 −/− mice are functional, it can be concluded that the suppressive function of Tregs depends upon HO-1-induced modulation of DCs rather than HO-1 expression by Tregs …