Cutting Edge: Nrf2 Regulates Neutrophil Recruitment and Accumulation in Skin during Contact Hypersensitivity

Abstract

Neutrophils are essential during contact hypersensitivity (CHS), a common skin allergic disease. NF-E2–related factor-2 (Nrf2) is a key regulator of redox balance and skin homeostasis playing a protective role in CHS. In this study, we investigated Nrf2 role in neutrophil recruitment during the sensitization phase of CHS. Comparing wild-type and Nrf2 knockout mice, we demonstrated that Nrf2 regulated dinitrochlorobenzene-induced xenoinflammation, notably neutrophil recruitment to sensitized skin. Nrf2 protective role was associated with high expression of antioxidant genes (ho-1, gclc, nqo1…) and decreased chemokine production (CCL2, CCL4, CCL11). Interestingly, skin sensitization induced CD36 upregulation in skin-resident macrophages. In vitro results confirmed that the transcription of cd36 gene in macrophages was dependent on Nrf2 and led to an improved capacity to phagocyte-damaged neutrophils by efferocytosis. Nrf2 emerges as a critical target in the sensitization phase of CHS regulating neutrophil recruitment and accumulation in the skin through antioxidant-dependent and -independent mechanisms.

CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation

“…Previous studies defined that PPARγ and NRF2 control CD36 expression levels [ 34 , 35 ] . By using an antagonist of PPARγ (GW9662), we found that myelin did not increase CD36 mRNA expression and protein abundance through PPARγ (Fig.…”

“…Female wild-type (wt) C57BL/6 J mice were purchased from Envigo. Nrf2 −/− mice were provided by the RIKEN BRC according to an MTA to Prof S. Kerdine-Römer [ 35 , 36 ]. Mice were housed in a pathogen-free facility and handled in accordance with the principles and procedures outlined in Council Directive 86/609/EEC.…”

“…Mice were housed in a pathogen-free facility and handled in accordance with the principles and procedures outlined in Council Directive 86/609/EEC. Genotyping was performed by PCR using genomic DNA that was isolated from tail snips as described previously [ 35 , 36 ]. Mice were maintained on a 12 h light/dark cycle with free access to water and a standard chow diet (Ssniff).…”

“…Noteworthy, CD36 internalizes oxLDL by a mechanism dependent on the binding of fatty acids [ 33 ], suggesting that the presence of fatty acids is important for recognition by CD36. On a transcriptional level, PPARγ and nuclear factor erythroid 2–related factor 2 (NRF2) are amongst the transcription factors that regulate CD36 abundance [ 34 , 35 ]. Altogether, these studies indicate that CD36 is a phagocytic receptor that plays a vital role in the uptake of fatty acid-containing substrates.…”

Cytokine profile in children with food allergy following liver transplantation

“…Firstly, tacrolimus down‐regulates the expression of MIP‐1b and may explain why the transplantation group had lower levels of MIP‐1b compared with the CLD group. The other factor is that allergy and asthma are associated with high MIP‐1b and even though these patients were treated with tacrolimus, MIP‐1b was elevated because of allergy. MIP‐1b is a pro‐inflammatory cytokine involved in immune responses toward inflammation and infection .…”