NRROS negatively regulates reactive oxygen species during host defence and autoimmunity

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Abstract

Reactive oxygen species (ROS) produced by phagocytes are essential for host defence against bacterial and fungal infections. Individuals with defective ROS production machinery develop chronic granulomatous disease1,2. Conversely, excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. Here we describe a protein, we termed negative regulator of ROS (NRROS), which limits ROS generation by phagocytes during inflammatory responses. NRROS expression in phagocytes can be repressed by inflammatory signals. NRROS-deficient phagocytes produce increased ROS upon inflammatory challenges, and mice lacking NRROS in their phagocytes show enhanced bactericidal activity against Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis owing to oxidative tissue damage in the central nervous system. Mechanistically, NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91phox and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway. Thus, NRROS provides a hitherto undefined mechanism for regulating ROS prodution—one that enables phagocytes to produce higher amounts of ROS, if required to control invading pathogens, while minimizing unwanted collateral tissue damage.

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Figure 1: NRROS is a negative regulator of ROS in phagocytes.
Figure 2: Increased ROS and bactericidal ability in NRROS-deficient phagocytes.
Figure 3: Mice with NRROS-deficient haematopoietic cells develop severe EAE owing to oxidative damage in the CNS.
Figure 4: NRROS regulates the activity of NOX2 oxidase complex in BMDMs.
Figure 5: NRROS promotes NOX2 degradation in the ER.

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Acknowledgements

We thank D. Seshasayee and H. Van Gorp for providing L929 condition media; J. Tao for helping with the screening of NRROS antibodies; C. Kuijl, J. R. Junutula (Genentech) and D. Monack (Stanford University) for providing S. typhimurium; W. Lee for providing L. monocytogenes and K. Huynh for providing dsRed E.coli; W. Forrest (Genentech) for help with statistical analysis; M. Roose-Girma, M. Schlatter and J. Aurellano (Genentech) for help with design and generation of Nrros conditional knockout construct and ES cells.

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Contributions

W.O. and R.N. devised the project and wrote the manuscript. R.N. designed and performed most of the experiments. K.W. contributed to Fig. 2h and Extended Data Figs 1e, 2a, b, N.O. contributed to Fig. 2f, S.R. contributed to Fig. 3a–g, C.E. contributed to Extended Data Fig. 5c–g, P.A.V. contributed to Extended Data Table 1, R.L. contributed to Fig. 5c, d. K.W., N.O., S.R. and C.E. helped to edit the manuscript. J.D. made the constructs used in Fig. 5 and Extended Data Fig. 8g, h. I.P. and J.D.V. contributed to EAE experiments in Fig. 3a, b, g and Extended Data Fig. 5c, f. A.S. and T.S. assisted in generating NRROS-specific antibodies (Fig. 1b and Extended Data Fig. 1c, e, h–j). P.C. carried out histopathology analyses and contributed to Extended Data Fig. 5d, e, g. R.H.S. and Z.M. assisted in microarray analysis and J.H. performed bioinformatics analysis (Extended Data Fig. 1a).

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Correspondence to Wenjun Ouyang.

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All authors are current or former employees of Genentech Inc.

Extended data figures and tables

Extended Data Figure 1 Murine NRROS is primarily expressed in immune tissues, especially in phagocytes.

a, BMDMs were either untreated or treated with IFN-γ, LPS or both. Heat map displays genes that were preferentially expressed in leukocytes and differentially regulated by the synergistic effects of both the treatments compared to either treatment alone. b, Analysis of Nrros expression in total RNA from different mouse tissues. Expression levels were normalized to Rpl19 (n = 4). c, Western blot analysis of NRROS protein expression in different mouse tissues. GAPDH used as loading control. d, Analysis of Nrros expression in total RNA from immune cells sorted from mouse spleen, normalized to Rpl19 (n = 3–5). e, Western blot analysis of NRROS protein expression in the indicated cells. HSP90 used as loading control. Mac, peritoneal macrophage; n.s., non-specific band observed only in lymphoid cells but not in macrophages with anti-NRROS antibody. f, Schematic of the strategy used to generate NRROS-deficient mice. g, Analysis of Nrros expression in total RNA from spleens of WT and KO mice (n = 5), normalized to Rpl19. h, Western blot analysis of NRROS protein expression in 3T3 cells overexpressing NRROS (NRROS-3T3) and control cells (GFP-3T3) to screen anti-NRROS antibody. Actin used as loading control. i, Western blot analysis of NRROS protein expression in WT and KO BMDMs. GAPDH as loading control. j, Western blot analysis of NRROS protein expression in immune tissues from WT and KO mice. Actin used as loading control. Although there was no detectable specific band in KO BMDMs, a weak, nonspecific band was observed in lymphoid cells from both WT and KO mice that was present just above the specific NRROS band. Error bars, s.e.m. Data in c, e and j are representative of at least three independent experiments.

Extended Data Figure 2 NRROS negatively regulates ROS production in various myeloid subsets.

ae, ROS production in thioglycollate-elicited peritoneal macrophages (a, b), neutrophils (c, d) and BMDM (e) stimulated with zymosan (zymo) (a, c) and phorbol 12-myristate 13-acetate (PMA) (b, d, e). Cells in a, b, e were primed with IFN-γ before ROS induction. Left panels, ROS kinetic plots of one representative experiment with three independent samples per group. Right panels, AUC from at least three independent experiments. f, ROS production in splenocytes from WT and KO mice (n = 3) stimulated with PMA in the presence of CM-H2DCFDA and analysed by FACS. MFI of CD11b+ Gr-1low/neg cells (left) and CD11b+ Gr-1high (right) are shown. Error bars, s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Unpaired Student’s t-test with Welch’s corrections (ae, left), paired Student’s t-test (ae, right), unpaired Student’s t-test (f). Data in f are representative of two independent experiments.

Extended Data Figure 3 NRROS negatively regulates ROS production in human monocyte-derived macrophages (MDMs).

a, b, Analysis of NRROS expression in total mRNA from human tissues (a) and cells purified from healthy donors (b) (n = 3). c, NRROS expression in MDMs stimulated as indicated (n = 3). d, NRROS expression in MDMs treated with non-targeting (Ctrl) or NRROS siRNA (siRNA). e, f, Kinetic graph of ROS production from cells shown in d. Cells were primed with IFN-γ and were then either unstimulated or stimulated with zymosan (e) or PMA (f). g, h, ROS production by IFN-γ-primed MDMs stimulated, in triplicate, with zymosan (g) and PMA (h) from three individual donors. Values at the peak production (60 min) are shown. Data in ad are normalized to endogenous control RPL19. Error bars, s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Unpaired Student’s t-test with (e, f) and without (g, h) Welch’s corrections. Data are representative of two independent experiments with three donors in each experiment.

Extended Data Figure 4 NRROS regulates ROS production and bactericidal activities of phagocytes but not phagocytosis or nitric oxide production by them.

ac, ROS production in IFN-γ-primed BMDMs stimulated with E. coli (a), S. typhimurium (b) and heat-killed L. monocytogenes (HKLM) (c). Averaged AUC from at least four independent experiments is plotted as bar graphs. d, In vitro E. coli killing by neutrophils purified from bone marrow of either WT or KO mice (n = 3). e, Nitric oxide (NO) in culture supernatant of BMDMs stimulated as indicated (n = 3). f, Representative histograms showing phagocytosis of serum-opsonized dsRed-E. coli by BMDMs. Thin line, untreated cells; thick line, treated cells. In the overlay histograms on the right: filled area, WT cells; thick line, NRROS-deficient cells. g, Left, NRROS expression in CD11b+ cells purified from spleens of uninfected WT and L. monocytogenes-infected WT and KO mice. Actin used as loading control. Right, densitometry analyses relative to actin. Error bars, s.e.m. **P < 0.01, ***P < 0.001. Paired (ac) or unpaired (d, g) Student’s t-test. Data in dg are representative of at least two independent experiments.

Extended Data Figure 5 Myeloid-specific deletion of NRROS leads to exacerbated EAE.

a, Schematic of the strategy used to generate Nrrosfl/fl mice. Numbers represent exons in Nrros gene. WT, Nrrosfl/flLysM-Creneg; KO, Nrrosfl/fl LysM-Crepos. b, Western blot analysis of NRROS protein in immune cells from WT and KO mice. Actin used as loading control. Mac, macrophage; PEC, peritoneal macrophage. ce, Clinical course (c), representative images of the spinal cord haematoxylin and eosin staining (d), and average histopathological lesion scores (day 30) (e) of EAE-induced WT (n = 20) and KO (n = 18) mice. Arrows in d indicate extensive myelinopathy of the lateral white matter tracts. Luxol fast blue staining of myelin is in blue. f, g, Clinical course (f) and lesion severity as assessed by histopathology on day 30 (g) of EAE-induced WT and KO mice administered with either vehicle control (ctrl) (n = 12) or a cocktail of ROS scavengers (n = 13 for WT and n = 14 for KO) every 12 h starting from day 9 (arrow) for the rest of the study. Error bars, s.e.m. *P < 0.05, ***P < 0.001. Two-way (c, f) or one-way (g) analysis of variance followed by Bonferroni’s post-hoc analysis, unpaired Student’s t-test (e). Data are representative of at least three (ce) and two (b) independent experiments. Data in f, g are combined from two independent experiments.

Extended Data Figure 6 NRROS regulates NOX2-mediated ROS but not mROS generation.

a, b, mROS production by IFN-γ-primed BMDMs from WT and NRROS-deficient (KO) mice stimulated with antimycin A (a) or rotenone (b) in the presence of MitoSOX. cg, IFN-γ-primed BMDMs were pre-treated for 1 h with antimycin A (c), DPI (d, e) or apocynin (f, g) before ROS induction by zymosan. (c, d, f). Left panels, ROS kinetic plots of a representative experiment with three independent samples per group; right panels, averaged AUC from three independent experiments. e, g, Dose response of DPI (e) or apocynin (g) treatment in WT and KO cells. Values at the peak of the curve are used for the bar graph. Error bars, s.e.m. *P < 0.05, **P < 0.01. Unpaired Student’s t-test with Welch’s corrections (c, d, f, left), paired Student’s t-test (c, d, f, right), unpaired Student’s t-test (e, g). Data are representative of two (a, b, e, g) or three (c, d, f) independent experiments.

Extended Data Figure 7 No difference between WT and NRROS-deficient BMDMs in expression and activation of the cytosolic members of NADPH oxidase complex.

a, Western blot analysis of p40phox, p47phox and p67phox in the lysates of BMDMs from WT and NRROS-deficient (KO) mice either unprimed (–) or primed (+) with IFN-γ. Actin used as loading control. b, c, phospho-p47phox (P-p47phox) and total p47phox (b), active Rac and total Rac (c) in IFN-γ-primed BMDMs stimulated with zymosan for the indicated time. Active Rac was immuoprecipitated and blotted. Total Rac in the lysates used as control. d, e, Taqman analysis of Cyba (p22phox) (d) and Cybb (NOX2) (e) expression in total RNA from BMDMs either primed with IFN-γ or left alone (Unprime). Expression levels were normalized to endogenous control, ribosomal protein L19 (Rpl19) (n = 3). fh, Top panels, NOX2 and p22phox expression in thioglycollate-elicited peritoneal macrophages (f), in splenocytes from mice infected with L. monocytogenes for 24 h (g) and in total CNS cells from EAE-induced mice on day 15 post-immunization (h). Bottom panels, densitometry analyses relative to actin (n = 3). Error bars, s.e.m. *P < 0.05, **P < 0.01 (unpaired Student’s t-test). Data are representative of three (ac) and two (fh) independent experiments.

Extended Data Figure 8 NRROS is an ER protein and regulates proteasome-mediated degradation of NOX2 and p22phox proteins.

ae, Densitometry analyses relative to actin of NOX2 (a, c), p22phox (b, d) and p62 (e) in IFN-γ-primed BMDMs from WT and KO cells treated with MG132 (a, b) or chloroquine (ce) for the indicated period (n = 3). p62 is shown as positive control for chloroquine treatment. f, Autoradiography showing immunoprecipitated NOX2 from BMDMs metabolically labelled with [35S]methionine for 1 h. The immunoprecipitates were subjected to Endo H treatment for 18 h. Total proteins in the flow-through lysates is shown as loading control. g, RAW cells retrovirally transduced to stably express GFP (GFP-RAW) or Flag–NRROS (Flag-NRROS-RAW) were stained with either isotype control (second column) or anti-Flag antibody (first and third columns). Cells were either non-permeabilized (top panels) or permeabilized (bottom panels). Overlay of the three populations is shown on the right. Thick line, Flag-NRROS-RAW cells stained with anti-Flag; filled area, GFP-RAW cells stained with anti-Flag; dashed line, Flag-NRROS-RAW cells stained with isotype control. h, RAW cells stably expressing Flag-tagged NRROS were stained with anti-Flag antibody (Flag) (green) and one of the indicated organelle markers (red), calnexin (top row) and Lamp1 (bottom row) and imaged by confocal microscopy. Colocalization of the two colours is depicted by yellow colour in the merged images on the right column. Error bars, s.e.m. *P < 0.05 (unpaired Student’s t-test). Data are representative of at least three independent experiments.

Extended Data Figure 9 NRROS does not regulate NOX2 through the HSP90–HSP70–CHIP pathway.

a, Western blot analysis of HSP90, HSP70 and CHIP in total lysates from IFN-γ-primed WT and KO BMDMs. Actin used as loading control. b, c, Zymosan-induced ROS production by IFN-γ-primed BMDMs treated with the HSP90 inhibitor radicicol at 5 μM (b) and 20 μM (c). A representative plot of kinetics of ROS production (three independently stimulated samples per group) from three independent experiments is shown. d, Left, NOX2, HSP90 and HSP70 expression in IFN-γ-primed BMDMs treated with the indicated dose of radicicol. Actin used as loading control. Right, densitometry analyses relative to actin from three experiments. Error bars, s.e.m. *P < 0.05, ***P < 0.001. Unpaired Student’s t-test with (b, c) and without (d) Welch’s corrections. Data in a are representative of three experiments.

Extended Data Table 1 Analysis of immune cell subsets in lymph node, spleen, thymus and blood of WT and KO mice

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Noubade, R., Wong, K., Ota, N. et al. NRROS negatively regulates reactive oxygen species during host defence and autoimmunity. Nature 509, 235–239 (2014). https://doi.org/10.1038/nature13152

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