Redox Control of Inflammation in Macrophages

Abstract

Macrophages are present throughout the human body, constitute important immune effector cells, and have variable roles in a great number of pathological, but also physiological, settings. It is apparent that macrophages need to adjust their activation profile toward a steadily changing environment that requires altering their phenotype, a process known as macrophage polarization. Formation of reactive oxygen species (ROS), derived from NADPH-oxidases, mitochondria, or NO-producing enzymes, are not necessarily toxic, but rather compose a network signaling system, known as redox regulation. Formation of redox signals in classically versus alternatively activated macrophages, their action and interaction at the level of key targets, and the resulting physiology still are insufficiently understood. We review the identity, source, and biological activities of ROS produced during macrophage activation, and discuss how they shape the key transcriptional responses evoked by hypoxia-inducible transcription factors, nuclear-erythroid 2-p45-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor-γ. We summarize the mechanisms how redox signals add to the process of macrophage polarization and reprogramming, how this is controlled by the interaction of macrophages with their environment, and addresses the outcome of the polarization process in health and disease. Future studies need to tackle the option whether we can use the knowledge of redox biology in macrophages to shape their mediator profile in pathophysiology, to accelerate healing in injured tissue, to fight the invading pathogens, or to eliminate settings of altered self in tumors.

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

“…Macrophages play an essential role in inflammation and increase oxygen uptake, resulting in the accumulation of ROS during inflammation (29). Similar to a previous study showing that Ninj1 blockade decreased the infiltration of macrophages in an experimental model of allergic encephalomyelitis (18), targeted depletion of the Ninj1 gene significantly reduced diabetesinduced infiltration of macrophages and the generation of ROS in macrophages.…”

Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers

“…To address whether such structural features might contribute to the LILRB1 interaction with classical HLA-I molecules, we analyzed with a soluble LILRB1-Fc fusion protein a panel of different HLA-I alleles transfected in the 721.221 cell line. As shown in expression of alleles containing cytoplasmic Cys residues, reported to promote HLA-I dimerization in exosomes [20,24]. Dimer formation, directly confirmed by western blotting, was associated with HLA-I molecules containing Cys 339 (i.e.…”

“…1, LILRB1-Fc stained .221-B7, -B27, -A2, and -A3 cells, marginally interacting with .221-B35 and -B51, irrespective of their HLA-I surface levels. This binding pattern appeared related with the expression of alleles containing cytoplasmic Cys residues, reported to promote HLA-I dimerization in exosomes [20,24]. Dimer formation, directly confirmed by western blotting, was associated with HLA-I molecules containing Cys 339 (i.e.…”

“…cell concentration and proliferation). In this regard, HLA-I conformation in exosomes has been shown to depend on the redox status [21], which might account for the differences observed in LILRB1 interaction with different primary monocytic cell types [24]. The possibility that HLA class Ia dimers in exosomes might contribute to engagement of the LILRB1 inhibitory receptor, controlling their clearance by monocytic cells deserves further attention.…”

An ethanol extract of <i>Aster yomena</i> (Kitam.) Honda inhibits lipopolysaccharide-induced inflammatory responses in murine RAW 264.7 macrophages

“…Another important component of inflammation is oxidative stress, which reflects an imbalance between the systemic manifestation of reactive oxygen species (ROS) and a biological system's ability to readily detoxify these reactive intermediates (11,12). Overproduction of ROS by activated macrophages is an important contributor to the manifestation of inflammation (13,14), and ROS are also involved in the production of inflammatory cytokines in LPS-stimulated macrophages (15).…”