Myeloid Heme Oxygenase-1 Regulates the Acute Inflammatory Response to Zymosan in the Mouse Air Pouch.

Heme oxygenase-1 (HO-1) is induced by many stimuli to modulate the activation and function of different cell types during innate immune responses. Although HO-1 has shown anti-inflammatory effects in different systems, there are few data on the contribution of myeloid HO-1 and its role in inflammatory processes is not well understood. To address this point, we have used HO-1M-KO mice with myeloid-restricted deletion of HO-1 to specifically investigate its influence on the acute inflammatory response to zymosan in vivo. In the mouse air pouch model, we have shown an exacerbated inflammation in HO-1M-KO mice with increased neutrophil infiltration accompanied by high levels of inflammatory mediators such as interleukin-1ß, tumor necrosis factor-α, and prostaglandin E2. The expression of the degradative enzyme matrix metalloproteinase-3 (MMP-3) was also enhanced. In addition, we observed higher levels of serum MMP-3 in HO-1M-KO mice compared with control mice, suggesting the presence of systemic inflammation. Altogether, these findings demonstrate that myeloid HO-1 plays an anti-inflammatory role in the acute response to zymosan in vivo and suggest the interest of this target to regulate inflammatory processes.

Effects of Nrf2 deficiency on bone microarchitecture in an experimental model of osteoporosis.

OBJECTIVE: Redox imbalance contributes to bone fragility. We have evaluated the in vivo role of nuclear factor erythroid derived 2-related factor-2 (Nrf2), an important regulator of cellular responses to oxidative stress, in bone metabolism using a model of postmenopausal osteoporosis. METHODS: Ovariectomy was performed in both wild-type and mice deficient in Nrf2 (Nrf2(-/-)). Bone microarchitecture was analyzed by µCT. Serum markers of bone metabolism were also measured. Reactive oxygen species production was determined using dihydrorhodamine 123. RESULTS: Sham-operated or ovariectomized Nrf2(-/-) mice exhibit a loss in trabecular bone mineral density in femur, accompanied by a reduction in cortical area in vertebrae. Nrf2 deficiency tended to increase osteoblastic markers and significantly enhanced osteoclastic markers in sham-operated animals indicating an increased bone turnover with a main effect on bone resorption. We have also shown an increased production of oxidative stress in bone marrow-derived cells from sham-operated or ovariectomized Nrf2(-/-) mice and a higher responsiveness of bone marrow-derived cells to osteoclastogenic stimuli in vitro. CONCLUSION: We have demonstrated in vivo a key role of Nrf2 in the maintenance of bone microarchitecture.

CO-releasing binuclear rhodium complexes as inhibitors of nitric oxide generation in stimulated macrophages.

Nontoxic CO-releasing dirhodium complexes act as inhibitors of NO in stimulated macrophage cells, suggesting that novel antiinflammatory treatments could involve the use of these types of binuclear complexes.

Heme oxygenase-1 regulates the progression of K/BxN serum transfer arthritis.

BACKGROUND: Heme oxygenase-1 (HO-1) is induced in many cell types as a defense mechanism against stress. We have investigated the possible role of endogenous HO-1 in the effector phase of arthritis using the K/BxN serum transfer model of arthritis in HO-1 heterozygous and homozygous knock-out mice. METHODOLOGY/PRINCIPAL FINDINGS: Arthritis was induced in C57/Black-6 xFVB (HO-1(+/+), HO-1(+/-) and HO-1(-/-)) mice by intraperitoneal injection of 150 µl serum from arthritic K/BxN mice at days 0 and 2. Blood was collected and animals were sacrificed at day 10. Histological analysis was performed in ankle sections. The levels of inflammatory mediators were measured in serum and paw homogenates by enzyme-linked immunosorbent assay or Multiplex technology. The incidence of arthritis was higher in HO-1(+/-) and HO-1(-/-) groups compared with HO-1(+/+). The inflammatory response was aggravated in HO-1(+/-) mice as shown by arthritic score and the migration of inflammatory cells that could be related to the enhancement of CXCL-1 production. In addition, the HO-1(+/-) group showed proteoglycan depletion significantly higher than HO-1(+/+) mice. Serum levels of matrix metalloproteinase-3, monocyte chemotactic protein-1, plasminogen activator inhibitor-1, E-selectin and intercellular adhesion molecule-1 were increased in arthritic HO-1(-/-) mice, whereas vascular endothelial growth factor and some cytokines such as interferon-γ showed a reduction compared to HO-1(+/+) or HO-1(+/-) mice. In addition, down-regulated gene expression of ferritin, glutathione S-reductase A1 and superoxide dismutase-2 was observed in the livers of arthritic HO-1(+/-) animals. CONCLUSION/SIGNIFICANCE: Endogenous HO-1 regulates the production of systemic and local inflammatory mediators and plays a protective role in K/BxN serum transfer arthritis.

Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease.

AIMS: Although oxidative stress participates in the etiopathogenesis of rheumatoid arthritis, its importance in this inflammatory disease has not been fully elucidated. In this study, we analyzed the relevance of the transcription factor Nrf2, master regulator of redox homeostasis, in the effector phase of an animal model of rheumatoid arthritis, using the transfer of serum from K/BxN transgenic mice to Nrf2(-/-) mice. RESULTS: Nrf2 deficiency accelerated the incidence of arthritis, and animals showed a widespread disease affecting both front and hind paws. Therefore, the inflammatory response was enhanced, with increased migration of leukocytes and joint destruction in front paws. We observed an increased production of tumor necrosis factor-α, interleukin-6, and CXCL-1 in the joint, with small changes in eicosanoid levels. Serum levels of CXCL-1 and receptor activator for nuclear factor κB ligand were enhanced and osteocalcin decreased in arthritic Nrf2(-/-) mice. The expression of cyclooxygenase-2, inducible nitric oxide synthase, and peroxynitrite in the joints was higher in Nrf2 deficiency, whereas heme oxygenase-1 was downregulated. INNOVATION: Nrf2 may be a therapeutic target for arthritis. CONCLUSION: Our results support a protective role of Nrf2 against joint inflammation and degeneration in arthritis.