The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

Abstract

Significance: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes ( MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. Recent Advances: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro-or anti-inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme-containing substrate and deliver it to HO-1. Critical Issues: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO-1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. Future Directions: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties.

Heme Oxygenase-1 Regulates Myeloid Cell Trafficking in AKI

“…16 Overexpression of IL-10 in RMNCs sorted from HBAC mice is likely associated with HO-1 overexpression in these mice, because the production of anti-inflammatory IL-10 appears to be tightly coupled and proportional to HO-1 expression levels. 14,22,36 DCs are the most abundant RMNCs in the quiescent kidney and are distributed throughout the parenchyma as an interconnected network of cells that likelycontribute to tissue homeostasis and serve as sentinels to tissue insult. 24,25,37 Macrophage depletion at the time of IRI ameliorates injury, whereas its depletion later between days 3 and 5 impairs the healing process, thus highlighting the phenotypic and functional shift that occurs temporally after the induction of the inflammatory process by injury.…”

“…12,13 Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme that regulates the inflammatory response to tissue injury. 14,15 Its induction is a protective response in renal IRI and other forms of AKI. 16,17 HO-1 expression decreases neutrophil infiltration after acute tissue injury.…”

“…18 In addition, HO-1 expression in DCs regulates their ability to undergo maturation and antigen presentation in lymphoid tissues. 14,[19][20][21] Because of its emerging role in immune regulation and transplantation, we hypothesized that HO-1 expression plays a critical role in the response to renal IRI by modulating the trafficking of myeloid cells into the kidney as well as controlling emigration of renal mononuclear cells (RMNCs), defined as hematopoietically derived CD11b + MHCII + cells residing within the renal parenchyma, to the peripheral lymphoid organs. We utilized transgenic mice with systemic (HO-1…”

Heme Oxygenase-1 in Kidney Health and Disease

“…RMPs include tissueresident leukocytes that perform homeostatic functions and those that transmigrate during inflammation or injury. The predominant functions of RMPs are phagocytosis (66), coordination of the immune response, and production of cytokines (58).…”

Novel Faces of Heme Oxygenase-1: Mechanisms and Therapeutic Potentials

“…Hull et al extensively elaborate on the involvement of HO-1 in the regulation of the functions of the mononuclear phagocyte system (6). The significance of TLR-dependent signaling is addressed, as well as the role of HO-1 played in different subpopulations of macrophages.…”