1 Supporting info Lung recovery from - PowerPoint Presentation

1. 1Supporting infoLung recovery from DNA damage induced by GO is dependent on size, dose, and inflammation profile Luis Augusto Visani de Luna1,2,3^, Thomas Loret1,2,3^, Alexander Fordham1,2,3, Atta Arshad1,2,3, Matthew Drummond1,2, Abbie Dodd1,2, Neus Lozano4, Kostas Kostarelos1,2,4 and Cyrill Bussy1,2,3* 1 Nanomedicine Lab 2.0, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK2 National Graphene Institute, The University of Manchester, Manchester, M13 9PL, UK3 Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK4 Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, 08193 Barcelona, Spain _______________________ ^These authors contributed equally to this work *Correspondence to: cyrill.bussy@manchester.ac.uk

2. 2USGOLGOABCD4 µm1 µm1 µmFigure S1. Structural and morphological characterization of USGO and LGO. A) and B) Height AFM images, C) and D) scanning electron micrographs.

3. 31 dControlUSGOLGOMWCNT7 d28 dFigure S2. Lung inflammation after single exposure to GOs. A) Immune cells infiltration and granulomatous formation in mice lungs at 1, 7 and 28 days after exposure to a single dose of carbon nanomaterials (USGO, LGO or MWCNT) compared to water for injection (= control). Lung infiltrates (Red arrow), granulomas formation (green arrows).

4. 4Figure S3. DNA damages in lung cells after single exposure. (A) Quantification of γ-H2Ax positive nuclei of epithelial cells (E-Cadherin+) in lung parenchyma (outside inflammatory infiltrates and excluding CD45+ cells). (B) Quantification of immune cells in mice lungs (number of CD45+ cells per FOV, n = 7) with immunostaining using Alexa Fluor® 594 labelled rat anti-mouse CD45 monoclonal antibody. A single exposure to high dose of carbon nanomaterials (USGO, LGO or MWCNTs) compared to water for injection (= control). Statistical significance: *P<0.05, **P<0.01, ***P<0.001. (n = 3).γ-H2AX+ cells in parenchyma(Relative to control)*****CD45+ Cells(Fold change to control)***********AB

5. 5γ-H2AX+ cells in parenchyma(Relative to control)γ-H2AX+ cells in parenchyma(Relative to control)High-doseLow-doseFigure S4. DNA damages in lung epithelial cells after repeated exposure. Quantification of γ-H2Ax positive nuclei of epithelial cells (E-Cadherin+) in lung parenchyma (outside inflammatory infiltrates and excluding CD45+ cells) was performed after repeated exposure (x3) to high dose (A) or low dose (B) of carbon nanomaterials (USGO, LGO or MWCNTs), compared to water for injection (= control). Statistical significance: *P<0.05, **P<0.01, ***P<0.001. (n = 3).AB******

6. 6Ligase IV (Fold change)Rad51 (Fold change)Ogg1 (Fold change)*********ABCFigure S5. DNA repair activity in whole lung tissue after repeated exposure to a high dose. (A - C) mRNA expression level measured by RT-qPCR for three genes coding for DNA repair proteins, expressed as fold change, in whole lung tissue lysate after exposure to carbon materials (USGO, LGO or MWCNTs) or negative control (water for injection). Statistical significance: *P<0.05, **P<0.01, ***P<0.001. (n = 6).

7. 7Figure S6. Published data on inflammation markers after repeated exposure to a high dose. (A - C) BALF cell counts measured after repeated exposure of mice to carbon materials (USGO, LGO or MWCNTs) or negative control (water for injection). (D) mRNA expression level measured by RT-qPCR for SAA3, expressed as fold change, in whole lung tissue lysate after exposure to carbon materials (USGO, LGO or MWCNTs) or negative control (water for injection). (E-H) Pro-inflammatory cytokines measured by ELISA multiplex. Statistical significance: *P<0.05, **P<0.01, ***P<0.001. (n = 6). In Loret T, de Luna LAV, Fordham A, Arshad A, Barr K, Lozano N, et al. Innate but Not Adaptive Immunity Regulates Lung Recovery from Chronic Exposure to Graphene Oxide Nanosheets. Adv Sci. 2022.Total macrophages****Multinucleated Macrophages**********************ABCSAA3 (Fold change)**********D*TNF-α (pg/mg)******IL-1β (pg/mg)EFIL-1α (pg/mg)**********GH*IL-6 (pg/mg)**************Neutrophils*

8. 8****HSP70 (Fold change)****HO-1 (Fold change)SOD-1 (Fold change)SOD-2 (Fold change)*****GSH (Fold change)ABCDEFigure S7. Published data on oxidative stress markers after repeated exposure to a high dose. (A - E) mRNA expression levels measured by RT-qPCR for different genes involved in the regulation of oxidative stress, expressed as fold change, in whole lung tissue lysate after exposure to carbon materials (USGO, LGO or MWCNTs) or negative control (water for injection). Statistical significance: *P<0.05, **P<0.01, ***P<0.001. (n = 6). In Loret T, de Luna LAV, Fordham A, Arshad A, Barr K, Lozano N, et al. Innate but Not Adaptive Immunity Regulates Lung Recovery from Chronic Exposure to Graphene Oxide Nanosheets. Adv Sci. 2022.*

9. 9Figure S8. Evaluation of DNA damages after repeated exposure to a high dose of GO sheets or MWCNTs. Lung parenchyma, infiltrates, granulomatous areas and nanomaterial deposition (brown colour) are highlighted in the H&E staining. The corresponding DNA damages after immunostaining (IHC) with γ-H2AX (DAB+ nuclei) and counterstaining with haematoxylin are highlighted. The framed inset pictures represent the same area of IHC without incubation with the primary antibody. The scale bar is equivalent to 20 µm.1 dControlUSGOLGOMWCNTH&EIHC84 dH&EIHC

10. 10Table S1. Summary of the physicochemical characterization of USGO and LGO sheets.

11. 11Table S2. List of PCR primers.GeneForward sequence (5'-3')Reverse sequence (5'-3')SAA-3AACTATGATGCTGCCCGGAGGCTCCATGTCCCGTGAACTTHSP70TTGGGCACCGATTACTGTCACCAGGCTACTGGAACACTGARAD51TCACGGTTAGAGCAGTGTGGACTCAGTTGCCGTGGTGAAALigase IVGCAGGGAGGTTCTTGGTCCTAGCAGCGTGCGGATACAACTAGSHGCCTGAGTCTAAAGGTGGTGATGACCTTGTCCCCTGCAAACHO-1CATAGCCCGGAGCCTGAATCCTCAGCATTCTCGGCTTGGAOGG1ACTGCATCTGCTTAATGGCCCGAAGGTCAGCACTGAACAGSOD1ACAAAGACTGGAAATGCTGGGAGCAGACTCAGACCACACAGGGAATGTSOD2AGGCTGTGAATGGAGTTCAGTGGTTAAGCACTCCTCAAGCAGGAGCAAGAPDHAGCCCTTGAGCCTTATTGTCTGCACTACGCCATAACTACC

12. (A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.590.74-0.31-0.30-0.28-0.38-0.92-0.340.700.890.620.890.770.730.04(B) Multi Mac0.591.000.31-0.86-0.76-0.78-0.75-0.74-0.610.630.760.650.710.540.54-0.60(C) Neutrophil0.740.311.000.110.02-0.21-0.19-0.62-0.390.140.520.220.390.370.180.01(D) SAA-3-0.31-0.860.111.000.610.520.580.420.54-0.52-0.46-0.71-0.56-0.60-0.590.52(E) TNF-a-0.30-0.760.020.611.000.920.920.640.48-0.49-0.67-0.14-0.48-0.12-0.200.78(F) IL-1b-0.28-0.78-0.210.520.921.000.920.600.59-0.30-0.60-0.05-0.330.000.000.86(G) IL-1a-0.38-0.75-0.190.580.920.921.000.660.76-0.29-0.62-0.07-0.41-0.23-0.100.88(H) IL-6-0.92-0.74-0.620.420.640.600.661.000.42-0.75-0.99-0.50-0.89-0.60-0.620.26(I) HSP70-0.34-0.61-0.390.540.480.590.760.421.000.10-0.30-0.13-0.19-0.43-0.010.77(J) HO-10.700.630.14-0.52-0.49-0.30-0.29-0.750.101.000.840.750.930.570.880.10(K) SOD10.890.760.52-0.46-0.67-0.60-0.62-0.99-0.300.841.000.550.920.570.67-0.21(L) SOD20.620.650.22-0.71-0.14-0.05-0.07-0.50-0.130.750.551.000.790.810.920.16(M) GSH0.890.710.39-0.56-0.48-0.33-0.41-0.89-0.190.930.920.791.000.780.910.02(N) RAD510.770.540.37-0.60-0.120.00-0.23-0.60-0.430.570.570.810.781.000.850.07(O) Ligase IV0.730.540.18-0.59-0.200.00-0.10-0.62-0.010.880.670.920.910.851.000.27(P) OGG10.04-0.600.010.520.780.860.880.260.770.10-0.210.160.020.070.271.00Table S3. Pearson R values (n = 6) for USGO, day 112(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.2210.0920.5500.5580.5940.4540.0100.5090.1250.0190.1880.0160.0730.1000.938(B) Multi Mac0.2210.5530.0290.0780.0670.0830.0900.1960.1810.0800.1600.1150.2660.2650.213(C) Neutrophil0.0920.5530.8360.9710.6900.7120.1920.4480.7890.2860.6770.4390.4740.7390.983(D) SAA-30.5500.0290.8360.1950.2930.2300.4060.2710.2850.3640.1130.2450.2040.2190.295(E) TNF-a0.5580.0780.9710.1950.0090.0090.1700.3350.3210.1490.7980.3390.8150.7110.070(F) IL-1b0.5940.0670.6900.2930.0090.0100.2040.2150.5600.2080.9230.5210.9980.9950.027(G) IL-1a0.4540.0830.7120.2300.0090.0100.1520.0780.5840.1870.9000.4210.6560.8570.021(H) IL-60.0100.0900.1920.4060.1700.2040.1520.4100.0870.0000.3150.0180.2100.1910.619(I) HSP700.5090.1960.4480.2710.3350.2150.0780.4100.8530.5580.8080.7160.3930.9820.071(J) HO-10.1250.1810.7890.2850.3210.5600.5840.0870.8530.0360.0880.0070.2420.0220.844(K) SOD10.0190.0800.2860.3640.1490.2080.1870.0000.5580.0360.2580.0090.2390.1410.685(L) SOD20.1880.1600.6770.1130.7980.9230.9000.3150.8080.0880.2580.0630.0480.0100.764(M) GSH0.0160.1150.4390.2450.3390.5210.4210.0180.7160.0070.0090.0630.0670.0120.972(N) RAD510.0730.2660.4740.2040.8150.9980.6560.2100.3930.2420.2390.0480.0670.0320.899(O) Ligase IV0.1000.2650.7390.2190.7110.9950.8570.1910.9820.0220.1410.0100.0120.0320.609(P) OGG10.9380.2130.9830.2950.0700.0270.0210.6190.0710.8440.6850.7640.9720.8990.609Table S4. P values (n = 6) for USGO, day 1

13. 13(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0090.0680.2570.9500.7220.6830.8270.3080.3930.3790.7110.7240.9440.2280.262(B) Multi Mac0.0090.3120.0580.5610.4940.4810.9720.1970.4340.4240.7370.6550.5870.3940.171(C) Neutrophil0.0680.3120.9740.2370.6160.8590.7060.5740.4970.3790.6060.7630.7690.0870.388(D) SAA-30.2570.0580.9740.1550.1910.6620.9390.5060.9130.9290.7090.8350.1280.8660.448(E) TNF-a0.9500.5610.2370.1550.0460.9930.7260.4870.8470.7730.9420.8130.3810.5430.947(F) IL-1b0.7220.4940.6160.1910.0460.5250.1820.7880.9700.8250.7620.7520.6540.5200.620(G) IL-1a0.6830.4810.8590.6620.9930.5250.0180.7690.8080.7140.9930.7090.9370.9500.405(H) IL-60.8270.9720.7060.9390.7260.1820.0180.9320.9810.6120.9500.6860.9320.9670.408(I) HSP700.3080.1970.5740.5060.4870.7880.7690.9320.0310.0140.0310.0210.8050.0780.051(J) HO-10.3930.4340.4970.9130.8470.9700.8080.9810.0310.0140.0100.0110.4280.0580.271(K) SOD10.3790.4240.3790.9290.7730.8250.7140.6120.0140.0140.0090.0300.8310.0330.210(L) SOD20.7110.7370.6060.7090.9420.7620.9930.9500.0310.0100.0090.0010.6520.0420.201(M) GSH0.7240.6550.7630.8350.8130.7520.7090.6860.0210.0110.0300.0010.7090.0760.148(N) RAD510.9440.5870.7690.1280.3810.6540.9370.9320.8050.4280.8310.6520.7090.7370.467(O) Ligase IV0.2280.3940.0870.8660.5430.5200.9500.9670.0780.0580.0330.0420.0760.7370.089(P) OGG10.2620.1710.3880.4480.9470.6200.4050.4080.0510.2710.2100.2010.1480.4670.089(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.920.780.55-0.030.19-0.210.12-0.50-0.43-0.44-0.20-0.190.04-0.58-0.55(B) Multi Mac0.921.000.500.800.300.35-0.36-0.02-0.61-0.40-0.41-0.18-0.230.28-0.43-0.64(C) Neutrophil0.780.501.000.02-0.57-0.260.090.20-0.29-0.35-0.44-0.27-0.16-0.16-0.75-0.44(D) SAA-30.550.800.021.000.660.62-0.230.04-0.340.06-0.050.200.110.690.09-0.39(E) TNF-a-0.030.30-0.570.661.000.820.000.18-0.36-0.10-0.15-0.04-0.120.440.32-0.04(F) IL-1b0.190.35-0.260.620.821.000.330.63-0.14-0.02-0.120.160.170.230.330.26(G) IL-1a-0.21-0.360.09-0.230.000.331.000.890.160.13-0.190.000.200.040.030.42(H) IL-60.12-0.020.200.040.180.630.891.000.05-0.01-0.260.030.21-0.050.020.42(I) HSP70-0.50-0.61-0.29-0.34-0.36-0.140.160.051.000.850.900.850.88-0.130.760.81(J) HO-1-0.43-0.40-0.350.06-0.10-0.020.13-0.010.851.000.900.920.910.400.800.54(K) SOD1-0.44-0.41-0.44-0.05-0.15-0.12-0.19-0.260.900.901.000.920.850.110.850.60(L) SOD2-0.20-0.18-0.270.20-0.040.160.000.030.850.920.921.000.970.240.830.61(M) GSH-0.19-0.23-0.160.11-0.120.170.200.210.880.910.850.971.000.200.760.67(N) RAD510.040.28-0.160.690.440.230.04-0.05-0.130.400.110.240.201.000.18-0.37(O) Ligase IV-0.58-0.43-0.750.090.320.330.030.020.760.800.850.830.760.181.000.75(P) OGG1-0.55-0.64-0.44-0.39-0.040.260.420.420.810.540.600.610.67-0.370.751.00Table S5. Pearson R values (n = 6) for USGO, day 7Table S6. P values (n = 6) for USGO, day 7

14. (A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.00-0.12-0.530.37-0.10-0.260.170.180.350.53-0.47-0.34-0.230.770.31-0.88(B) Multi Mac-0.121.000.240.55-0.03-0.33-0.03-0.22-0.510.200.060.020.08-0.53-0.50-0.33(C) Neutrophil-0.530.241.00-0.030.590.66-0.21-0.38-0.40-0.470.230.17-0.21-0.06-0.230.78(D) SAA-30.370.55-0.031.000.700.220.050.02-0.620.46-0.96-0.95-0.860.08-0.75-0.39(E) TNF-a-0.10-0.030.590.701.000.82-0.26-0.32-0.67-0.17-0.55-0.67-0.89-0.05-0.700.31(F) IL-1b-0.26-0.330.660.220.821.00-0.56-0.57-0.45-0.66-0.07-0.34-0.67-0.13-0.300.66(G) IL-1a0.17-0.03-0.210.05-0.26-0.561.000.970.520.82-0.320.240.370.46-0.09-0.45(H) IL-60.18-0.22-0.380.02-0.32-0.570.971.000.590.78-0.330.190.380.38-0.09-0.46(I) HSP700.35-0.51-0.40-0.62-0.67-0.450.520.591.000.250.280.610.650.630.76-0.34(J) HO-10.530.20-0.470.46-0.17-0.660.820.780.251.00-0.64-0.200.060.47-0.21-0.83(K) SOD1-0.470.060.23-0.96-0.55-0.07-0.32-0.330.28-0.641.000.840.71-0.240.690.54(L) SOD2-0.340.020.17-0.95-0.67-0.340.240.190.61-0.200.841.000.910.110.710.29(M) GSH-0.230.08-0.21-0.86-0.89-0.670.370.380.650.060.710.911.000.010.630.02(N) RAD510.77-0.53-0.060.08-0.05-0.130.460.380.630.47-0.240.110.011.000.43-0.58(O) Ligase IV0.31-0.50-0.23-0.75-0.70-0.30-0.09-0.090.76-0.210.690.710.630.431.00-0.14(P) OGG1-0.88-0.330.78-0.390.310.66-0.45-0.46-0.34-0.830.540.290.02-0.58-0.141.0014(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.8140.2820.5440.8500.6210.7450.7380.4960.2780.3430.5150.6580.1290.6060.046(B) Multi Mac0.8140.6470.3420.9570.5280.9560.6710.3040.7050.9100.9650.8850.3540.3900.591(C) Neutrophil0.2820.6470.9570.2160.1530.6960.4630.4340.3480.6640.7520.6910.9190.7070.116(D) SAA-30.5440.3420.9570.1920.7210.9330.9730.2650.4370.0110.0120.0630.9010.1420.517(E) TNF-a0.8500.9570.2160.1920.0470.6180.5370.1460.7440.2600.1460.0180.9370.1910.615(F) IL-1b0.6210.5280.1530.7210.0470.2430.2380.3720.1570.8930.5080.1420.8400.6200.228(G) IL-1a0.7450.9560.6960.9330.6180.2430.0020.2860.0480.5420.6520.4640.4340.8890.446(H) IL-60.7380.6710.4630.9730.5370.2380.0020.2190.0670.5180.7250.4640.5230.8910.435(I) HSP700.4960.3040.4340.2650.1460.3720.2860.2190.6300.5860.1950.1600.2530.1350.572(J) HO-10.2780.7050.3480.4370.7440.1570.0480.0670.6300.1740.7010.9150.4240.7310.081(K) SOD10.3430.9100.6640.0110.2600.8930.5420.5180.5860.1740.0360.1150.6920.1940.343(L) SOD20.5150.9650.7520.0120.1460.5080.6520.7250.1950.7010.0360.0130.8620.1800.633(M) GSH0.6580.8850.6910.0630.0180.1420.4640.4640.1600.9150.1150.0130.9910.2500.980(N) RAD510.1290.3540.9190.9010.9370.8400.4340.5230.2530.4240.6920.8620.9910.4710.307(O) Ligase IV0.6060.3900.7070.1420.1910.6200.8890.8910.1350.7310.1940.1800.2500.4710.821(P) OGG10.0460.5910.1160.5170.6150.2280.4460.4350.5720.0810.3430.6330.9800.3070.821Table S7. Pearson R values (n = 6) for USGO, day 28Table S8. P values (n = 6) for USGO, day 28

15. 15(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.770.84-0.510.250.09-0.120.010.450.47-0.410.600.320.710.19-0.06(B) Multi Mac0.771.000.92-0.440.370.390.200.300.610.63-0.160.580.270.460.21-0.36(C) Neutrophil0.840.921.00-0.450.430.060.140.150.490.47-0.190.440.100.490.19-0.45(D) SAA-3-0.51-0.44-0.451.000.65-0.210.770.610.240.29-0.070.140.41-0.190.730.65(E) TNF-a0.250.370.430.651.00-0.040.900.690.660.70-0.190.510.480.180.900.26(F) IL-1b0.090.390.06-0.21-0.041.000.170.630.650.64-0.430.650.650.850.440.40(G) IL-1a-0.120.200.140.770.900.171.000.820.630.67-0.080.410.480.020.870.29(H) IL-60.010.300.150.610.690.630.821.000.900.88-0.510.730.800.540.980.52(I) HSP700.450.610.490.240.660.650.630.901.000.98-0.680.930.850.770.830.39(J) HO-10.470.630.470.290.700.640.670.880.981.00-0.570.940.880.660.860.42(K) SOD1-0.41-0.16-0.19-0.07-0.19-0.43-0.08-0.51-0.68-0.571.00-0.74-0.73-0.94-0.51-0.58(L) SOD20.600.580.440.140.510.650.410.730.930.94-0.741.000.930.800.740.54(M) GSH0.320.270.100.410.480.650.480.800.850.88-0.730.931.000.690.830.79(N) RAD510.710.460.49-0.190.180.850.020.540.770.66-0.940.800.691.000.410.34(O) Ligase IV0.190.210.190.730.900.440.870.980.830.86-0.510.740.830.411.000.64(P) OGG1-0.06-0.36-0.450.650.260.400.290.520.390.42-0.580.540.790.340.641.00(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0710.0380.3840.6330.8650.8250.9780.3750.3520.4210.2050.5310.1830.7560.922(B) Multi Mac0.0710.0100.4640.4640.4460.7040.5590.2030.1810.7670.2330.6100.4370.7360.550(C) Neutrophil0.0380.0100.4510.3910.9170.7870.7800.3280.3420.7130.3870.8470.4010.7630.445(D) SAA-30.3840.4640.4510.2380.7410.1280.2780.6980.6410.9080.8240.4920.7590.1590.237(E) TNF-a0.6330.4640.3910.2380.9440.0140.1320.1570.1230.7110.3050.3310.7710.0390.676(F) IL-1b0.8650.4460.9170.7410.9440.7550.1800.1580.1700.3970.1600.1660.0650.4600.509(G) IL-1a0.8250.7040.7870.1280.0140.7550.0450.1840.1470.8840.4190.3310.9770.0550.641(H) IL-60.9780.5590.7800.2780.1320.1800.0450.0160.0220.2980.0960.0590.3520.0050.371(I) HSP700.3750.2030.3280.6980.1570.1580.1840.0160.0010.1340.0080.0300.1270.0790.512(J) HO-10.3520.1810.3420.6410.1230.1700.1470.0220.0010.2370.0050.0220.2280.0650.480(K) SOD10.4210.7670.7130.9080.7110.3970.8840.2980.1340.2370.0950.0990.0180.3800.304(L) SOD20.2050.2330.3870.8240.3050.1600.4190.0960.0080.0050.0950.0060.1050.1550.349(M) GSH0.5310.6100.8470.4920.3310.1660.3310.0590.0300.0220.0990.0060.1980.0820.109(N) RAD510.1830.4370.4010.7590.7710.0650.9770.3520.1270.2280.0180.1050.1980.4940.579(O) Ligase IV0.7560.7360.7630.1590.0390.4600.0550.0050.0790.0650.3800.1550.0820.4940.247(P) OGG10.9220.5500.4450.2370.6760.5090.6410.3710.5120.4800.3040.3490.1090.5790.247Table S9. Pearson R values (n = 6) for USGO, day 84Table S10. P values (n = 6) for USGO, day 84

16. (A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.880.290.000.520.090.610.40-0.780.56-0.07-0.03-0.050.56-0.20-0.37(B) Multi Mac0.881.000.11-0.070.380.440.390.42-0.820.420.290.280.240.560.21-0.10(C) Neutrophil0.290.111.000.900.630.010.580.39-0.650.800.290.36-0.20-0.320.01-0.59(D) SAA-30.00-0.070.901.000.530.240.450.42-0.490.770.500.590.01-0.490.30-0.26(E) TNF-a0.520.380.630.531.000.400.980.92-0.580.58-0.040.03-0.54-0.410.16-0.69(F) IL-1b0.090.440.010.240.401.000.280.70-0.380.180.630.630.26-0.280.930.20(G) IL-1a0.610.390.580.450.980.281.000.86-0.550.60-0.19-0.10-0.55-0.27-0.02-0.67(H) IL-60.400.420.390.420.920.700.861.00-0.490.420.120.18-0.38-0.450.47-0.45(I) HSP70-0.78-0.82-0.65-0.49-0.58-0.38-0.55-0.491.00-0.79-0.50-0.53-0.18-0.26-0.240.32(J) HO-10.560.420.800.770.580.180.600.42-0.791.000.380.480.180.090.06-0.19(K) SOD1-0.070.290.290.50-0.040.63-0.190.12-0.500.381.000.990.71-0.040.790.38(L) SOD2-0.030.280.360.590.030.63-0.100.18-0.530.480.991.000.70-0.060.780.38(M) GSH-0.050.24-0.200.01-0.540.26-0.55-0.38-0.180.180.710.701.000.510.400.84(N) RAD510.560.56-0.32-0.49-0.41-0.28-0.27-0.45-0.260.09-0.04-0.060.511.00-0.370.35(O) Ligase IV-0.200.210.010.300.160.93-0.020.47-0.240.060.790.780.40-0.371.000.32(P) OGG1-0.37-0.10-0.59-0.26-0.690.20-0.67-0.450.32-0.190.380.380.840.350.321.0016(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0200.5810.9960.2870.8600.1990.4300.0650.2490.9010.9490.9210.2520.7010.474(B) Multi Mac0.0200.8390.8990.4630.3850.4440.4100.0480.4030.5820.5890.6460.2480.6930.848(C) Neutrophil0.5810.8390.0150.1780.9880.2270.4410.1640.0570.5720.4830.6980.5400.9830.222(D) SAA-30.9960.8990.0150.2750.6530.3680.4120.3200.0710.3110.2220.9810.3260.5630.614(E) TNF-a0.2870.4630.1780.2750.4280.0010.0090.2310.2310.9440.9480.2690.4230.7660.131(F) IL-1b0.8600.3850.9880.6530.4280.5980.1190.4590.7400.1830.1780.6140.5970.0080.710(G) IL-1a0.1990.4440.2270.3680.0010.5980.0280.2630.2070.7260.8520.2540.5980.9770.147(H) IL-60.4300.4100.4410.4120.0090.1190.0280.3180.4110.8160.7350.4600.3670.3520.374(I) HSP700.0650.0480.1640.3200.2310.4590.2630.3180.0610.3140.2790.7270.6190.6460.543(J) HO-10.2490.4030.0570.0710.2310.7400.2070.4110.0610.4590.3310.7330.8650.9040.719(K) SOD10.9010.5820.5720.3110.9440.1830.7260.8160.3140.4590.0000.1160.9440.0600.460(L) SOD20.9490.5890.4830.2220.9480.1780.8520.7350.2790.3310.0000.1210.9160.0700.463(M) GSH0.9210.6460.6980.9810.2690.6140.2540.4600.7270.7330.1160.1210.2970.4290.036(N) RAD510.2520.2480.5400.3260.4230.5970.5980.3670.6190.8650.9440.9160.2970.4740.495(O) Ligase IV0.7010.6930.9830.5630.7660.0080.9770.3520.6460.9040.0600.0700.4290.4740.533(P) OGG10.4740.8480.2220.6140.1310.7100.1470.3740.5430.7190.4600.4630.0360.4950.533Table S11. Pearson R values (n = 6) for LGO, day 1Table S12. P values (n = 6) for LGO, day 1

17. 17(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.760.66-0.57-0.87-0.920.02-0.890.33-0.38-0.24-0.52-0.11-0.39-0.56-0.69(B) Multi Mac0.761.000.30-0.95-0.40-0.560.34-0.460.51-0.08-0.36-0.490.10-0.80-0.56-0.73(C) Neutrophil0.660.301.00-0.14-0.69-0.76-0.11-0.78-0.26-0.86-0.53-0.69-0.52-0.34-0.86-0.55(D) SAA-3-0.57-0.95-0.141.000.250.39-0.230.30-0.53-0.130.360.39-0.210.830.480.60(E) TNF-a-0.87-0.40-0.690.251.000.940.360.99-0.140.330.130.380.180.030.390.38(F) IL-1b-0.92-0.56-0.760.390.941.000.050.970.010.480.420.660.400.300.560.42(G) IL-1a0.020.34-0.11-0.230.360.051.000.27-0.24-0.25-0.46-0.49-0.40-0.52-0.16-0.09(H) IL-6-0.89-0.46-0.780.300.990.970.271.00-0.050.450.280.520.290.160.520.43(I) HSP700.330.51-0.26-0.53-0.140.01-0.24-0.051.000.520.590.490.89-0.070.13-0.55(J) HO-1-0.38-0.08-0.86-0.130.330.48-0.250.450.521.000.560.700.710.270.750.40(K) SOD1-0.24-0.36-0.530.360.130.42-0.460.280.590.561.000.940.800.730.700.07(L) SOD2-0.52-0.49-0.690.390.380.66-0.490.520.490.700.941.000.810.700.770.26(M) GSH-0.110.10-0.52-0.210.180.40-0.400.290.890.710.800.811.000.220.42-0.24(N) RAD51-0.39-0.80-0.340.830.030.30-0.520.16-0.070.270.730.700.221.000.740.54(O) Ligase IV-0.56-0.56-0.860.480.390.56-0.160.520.130.750.700.770.420.741.000.70(P) OGG1-0.69-0.73-0.550.600.380.42-0.090.43-0.550.400.070.26-0.240.540.701.00(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0820.1540.2400.0230.0090.9680.0160.5290.4570.6510.2950.8360.4460.2430.132(B) Multi Mac0.0820.5580.0040.4260.2500.5130.3630.3020.8820.4890.3250.8440.0550.2430.097(C) Neutrophil0.1540.5580.7880.1320.0830.8410.0690.6250.0290.2790.1300.2880.5110.0280.260(D) SAA-30.2400.0040.7880.6300.4470.6550.5640.2790.8010.4840.4470.6940.0400.3350.212(E) TNF-a0.0230.4260.1320.6300.0050.4850.0000.7920.5210.8000.4580.7330.9480.4440.458(F) IL-1b0.0090.2500.0830.4470.0050.9200.0010.9860.3350.4040.1540.4280.5650.2460.406(G) IL-1a0.9680.5130.8410.6550.4850.9200.6040.6500.6280.3630.3270.4360.2940.7550.865(H) IL-60.0160.3630.0690.5640.0000.0010.6040.9190.3770.5880.2940.5750.7620.2880.401(I) HSP700.5290.3020.6250.2790.7920.9860.6500.9190.2870.2170.3250.0170.8930.8090.261(J) HO-10.4570.8820.0290.8010.5210.3350.6280.3770.2870.2500.1240.1160.6060.0840.436(K) SOD10.6510.4890.2790.4840.8000.4040.3630.5880.2170.2500.0060.0580.0990.1220.895(L) SOD20.2950.3250.1300.4470.4580.1540.3270.2940.3250.1240.0060.0530.1210.0740.618(M) GSH0.8360.8440.2880.6940.7330.4280.4360.5750.0170.1160.0580.0530.6800.4130.650(N) RAD510.4460.0550.5110.0400.9480.5650.2940.7620.8930.6060.0990.1210.6800.0920.264(O) Ligase IV0.2430.2430.0280.3350.4440.2460.7550.2880.8090.0840.1220.0740.4130.0920.122(P) OGG10.1320.0970.2600.2120.4580.4060.8650.4010.2610.4360.8950.6180.6500.2640.122Table S13. Pearson R values (n = 6) for LGO, day 7Table S14. P values (n = 6) for LGO, day 7

18. 18(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.58-0.200.10-0.02-0.530.570.39-0.150.840.130.240.530.020.410.16(B) Multi Mac0.581.00-0.370.100.53-0.480.91-0.270.410.47-0.58-0.30-0.110.210.82-0.32(C) Neutrophil-0.20-0.371.000.230.12-0.47-0.48-0.49-0.32-0.12-0.10-0.35-0.46-0.72-0.20-0.54(D) SAA-30.100.100.231.000.70-0.610.13-0.18-0.360.540.210.30-0.250.400.05-0.59(E) TNF-a-0.020.530.120.701.00-0.660.35-0.70-0.040.18-0.36-0.15-0.530.200.32-0.77(F) IL-1b-0.53-0.48-0.47-0.61-0.661.00-0.300.430.34-0.580.150.090.190.26-0.310.62(G) IL-1a0.570.91-0.480.130.35-0.301.00-0.030.600.60-0.53-0.28-0.120.460.92-0.27(H) IL-60.39-0.27-0.49-0.18-0.700.43-0.031.00-0.190.370.700.680.820.37-0.240.79(I) HSP70-0.150.41-0.32-0.36-0.040.340.60-0.191.00-0.13-0.78-0.71-0.500.260.75-0.23(J) HO-10.840.47-0.120.540.18-0.580.600.37-0.131.000.190.300.280.350.45-0.13(K) SOD10.13-0.58-0.100.21-0.360.15-0.530.70-0.780.191.000.930.740.16-0.760.60(L) SOD20.24-0.30-0.350.30-0.150.09-0.280.68-0.710.300.931.000.770.39-0.600.58(M) GSH0.53-0.11-0.46-0.25-0.530.19-0.120.82-0.500.280.740.771.000.08-0.410.87(N) RAD510.020.21-0.720.400.200.260.460.370.260.350.160.390.081.000.240.06(O) Ligase IV0.410.82-0.200.050.32-0.310.92-0.240.750.45-0.76-0.60-0.410.241.00-0.48(P) OGG10.16-0.32-0.54-0.59-0.770.62-0.270.79-0.23-0.130.600.580.870.06-0.481.00(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.2260.7100.8490.9660.2780.2350.4440.7720.0360.8130.6510.2780.9740.4250.763(B) Multi Mac0.2260.4640.8510.2850.3320.0120.6090.4150.3450.2290.5620.8370.6850.0450.542(C) Neutrophil0.7100.4640.6600.8170.3410.3390.3230.5400.8230.8560.4910.3560.1100.7080.273(D) SAA-30.8490.8510.6600.1190.1950.8100.7360.4820.2710.6910.5580.6360.4370.9250.216(E) TNF-a0.9660.2850.8170.1190.1550.4980.1190.9450.7260.4800.7740.2800.7060.5350.075(F) IL-1b0.2780.3320.3410.1950.1550.5660.3970.5110.2270.7720.8680.7230.6150.5530.190(G) IL-1a0.2350.0120.3390.8100.4980.5660.9570.2110.2080.2820.5940.8260.3620.0080.599(H) IL-60.4440.6090.3230.7360.1190.3970.9570.7260.4650.1190.1400.0480.4660.6460.062(I) HSP700.7720.4150.5400.4820.9450.5110.2110.7260.8110.0660.1100.3130.6120.0850.659(J) HO-10.0360.3450.8230.2710.7260.2270.2080.4650.8110.7190.5580.5860.4960.3700.805(K) SOD10.8130.2290.8560.6910.4800.7720.2820.1190.0660.7190.0060.0920.7570.0810.205(L) SOD20.6510.5620.4910.5580.7740.8680.5940.1400.1100.5580.0060.0700.4450.2070.228(M) GSH0.2780.8370.3560.6360.2800.7230.8260.0480.3130.5860.0920.0700.8770.4260.023(N) RAD510.9740.6850.1100.4370.7060.6150.3620.4660.6120.4960.7570.4450.8770.6490.916(O) Ligase IV0.4250.0450.7080.9250.5350.5530.0080.6460.0850.3700.0810.2070.4260.6490.334(P) OGG10.7630.5420.2730.2160.0750.1900.5990.0620.6590.8050.2050.2280.0230.9160.334Table S15. Pearson R values (n = 6) for LGO, day 28Table S16. P values (n = 6) for LGO, day 28

19. (A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.800.90-0.40-0.330.27-0.330.51-0.76-0.420.65-0.230.050.29-0.320.26(B) Multi Mac0.801.000.97-0.12-0.450.41-0.020.41-0.95-0.530.64-0.47-0.06-0.09-0.200.38(C) Neutrophil0.900.971.00-0.32-0.360.45-0.040.55-0.94-0.620.60-0.50-0.150.04-0.360.23(D) SAA-3-0.40-0.12-0.321.00-0.26-0.56-0.42-0.590.250.650.240.550.65-0.370.840.73(E) TNF-a-0.33-0.45-0.36-0.261.00-0.370.400.080.48-0.26-0.89-0.38-0.53-0.56-0.61-0.54(F) IL-1b0.270.410.45-0.56-0.371.000.400.65-0.65-0.660.17-0.51-0.580.40-0.33-0.48(G) IL-1a-0.33-0.02-0.04-0.420.400.401.000.04-0.04-0.52-0.61-0.76-0.75-0.38-0.58-0.62(H) IL-60.510.410.55-0.590.080.650.041.00-0.61-0.830.02-0.55-0.650.17-0.58-0.48(I) HSP70-0.76-0.95-0.940.250.48-0.65-0.04-0.611.000.66-0.590.530.24-0.060.25-0.16(J) HO-1-0.42-0.53-0.620.65-0.26-0.66-0.52-0.830.661.000.190.920.860.200.810.54(K) SOD10.650.640.600.24-0.890.17-0.610.02-0.590.191.000.350.610.450.480.72(L) SOD2-0.23-0.47-0.500.55-0.38-0.51-0.76-0.550.530.920.351.000.860.450.820.50(M) GSH0.05-0.06-0.150.65-0.53-0.58-0.75-0.650.240.860.610.861.000.250.810.84(N) RAD510.29-0.090.04-0.37-0.560.40-0.380.17-0.060.200.450.450.251.000.18-0.12(O) Ligase IV-0.32-0.20-0.360.84-0.61-0.33-0.58-0.580.250.810.480.820.810.181.000.68(P) OGG10.260.380.230.73-0.54-0.48-0.62-0.48-0.160.540.720.500.84-0.120.681.0019(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0580.0140.4310.5180.6030.5250.2990.0820.4100.1640.6640.9240.5820.5380.622(B) Multi Mac0.0580.0020.8210.3680.4180.9730.4250.0030.2750.1690.3450.9040.8720.7100.463(C) Neutrophil0.0140.0020.5300.4790.3650.9340.2600.0050.1900.2120.3090.7780.9450.4890.657(D) SAA-30.4310.8210.5300.6170.2440.4030.2200.6340.1650.6530.2560.1600.4770.0360.098(E) TNF-a0.5180.3680.4790.6170.4690.4360.8780.3330.6240.0170.4600.2810.2530.1990.265(F) IL-1b0.6030.4180.3650.2440.4690.4340.1640.1640.1560.7490.3010.2310.4270.5230.334(G) IL-1a0.5250.9730.9340.4030.4360.4340.9420.9440.2920.1970.0830.0890.4510.2240.194(H) IL-60.2990.4250.2600.2200.8780.1640.9420.2020.0430.9640.2630.1610.7430.2330.330(I) HSP700.0820.0030.0050.6340.3330.1640.9440.2020.1520.2140.2820.6520.9120.6370.759(J) HO-10.4100.2750.1900.1650.6240.1560.2920.0430.1520.7250.0090.0270.6990.0510.272(K) SOD10.1640.1690.2120.6530.0170.7490.1970.9640.2140.7250.5010.1970.3680.3350.110(L) SOD20.6640.3450.3090.2560.4600.3010.0830.2630.2820.0090.5010.0270.3700.0450.315(M) GSH0.9240.9040.7780.1600.2810.2310.0890.1610.6520.0270.1970.0270.6330.0490.035(N) RAD510.5820.8720.9450.4770.2530.4270.4510.7430.9120.6990.3680.3700.6330.7280.828(O) Ligase IV0.5380.7100.4890.0360.1990.5230.2240.2330.6370.0510.3350.0450.0490.7280.136(P) OGG10.6220.4630.6570.0980.2650.3340.1940.3300.7590.2720.1100.3150.0350.8280.136Table S17. Pearson R values (n = 6) for LGO, day 84Table S18. P values (n = 6) for LGO, day 84

20. (A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.870.74-0.40-0.490.490.10-0.49-0.71-0.24-0.05-0.360.05-0.310.310.48(B) Multi Mac0.871.000.91-0.44-0.230.040.37-0.48-0.70-0.57-0.46-0.64-0.35-0.590.250.65(C) Neutrophil0.740.911.00-0.29-0.39-0.060.16-0.69-0.69-0.49-0.52-0.56-0.34-0.380.420.36(D) SAA-3-0.40-0.44-0.291.000.260.070.110.440.810.790.600.840.520.700.66-0.36(E) TNF-a-0.49-0.23-0.390.261.00-0.600.800.860.65-0.13-0.13-0.02-0.35-0.31-0.220.38(F) IL-1b0.490.04-0.060.07-0.601.00-0.46-0.19-0.140.580.760.480.850.380.22-0.05(G) IL-1a0.100.370.160.110.80-0.461.000.580.27-0.33-0.26-0.28-0.44-0.510.100.69(H) IL-6-0.49-0.48-0.690.440.86-0.190.581.000.810.300.360.380.080.06-0.130.15(I) HSP70-0.71-0.70-0.690.810.65-0.140.270.811.000.620.510.720.350.430.13-0.18(J) HO-1-0.24-0.57-0.490.79-0.130.58-0.330.300.621.000.930.990.890.880.49-0.52(K) SOD1-0.05-0.46-0.520.60-0.130.76-0.260.360.510.931.000.900.930.710.34-0.30(L) SOD2-0.36-0.64-0.560.84-0.020.48-0.280.380.720.990.901.000.850.860.44-0.51(M) GSH0.05-0.35-0.340.52-0.350.85-0.440.080.350.890.930.851.000.660.33-0.27(N) RAD51-0.31-0.59-0.380.70-0.310.38-0.510.060.430.880.710.860.661.000.55-0.84(O) Ligase IV0.310.250.420.66-0.220.220.10-0.130.130.490.340.440.330.551.00-0.23(P) OGG10.480.650.36-0.360.38-0.050.690.15-0.18-0.52-0.30-0.51-0.27-0.84-0.231.0020(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0230.0950.4300.3300.3220.8470.3220.1120.6420.9270.4800.9290.5530.5470.337(B) Multi Mac0.0230.0110.3850.6670.9370.4650.3330.1250.2380.3630.1700.5010.2190.6280.164(C) Neutrophil0.0950.0110.5790.4420.9150.7550.1260.1320.3190.2900.2520.5070.4550.4070.477(D) SAA-30.4300.3850.5790.6220.9000.8370.3840.0490.0600.2120.0360.2870.1200.1550.488(E) TNF-a0.3300.6670.4420.6220.2120.0570.0280.1590.8060.8110.9690.4910.5500.6690.457(F) IL-1b0.3220.9370.9150.9000.2120.3590.7200.7920.2320.0820.3380.0320.4640.6720.930(G) IL-1a0.8470.4650.7550.8370.0570.3590.2310.6090.5270.6160.5940.3780.3000.8560.132(H) IL-60.3220.3330.1260.3840.0280.7200.2310.0500.5580.4790.4550.8780.9050.8020.773(I) HSP700.1120.1250.1320.0490.1590.7920.6090.0500.1890.3030.1070.4970.3930.8040.727(J) HO-10.6420.2380.3190.0600.8060.2320.5270.5580.1890.0070.0000.0190.0210.3260.290(K) SOD10.9270.3630.2900.2120.8110.0820.6160.4790.3030.0070.0140.0070.1140.5160.567(L) SOD20.4800.1700.2520.0360.9690.3380.5940.4550.1070.0000.0140.0330.0300.3840.302(M) GSH0.9290.5010.5070.2870.4910.0320.3780.8780.4970.0190.0070.0330.1550.5170.608(N) RAD510.5530.2190.4550.1200.5500.4640.3000.9050.3930.0210.1140.0300.1550.2590.036(O) Ligase IV0.5470.6280.4070.1550.6690.6720.8560.8020.8040.3260.5160.3840.5170.2590.664(P) OGG10.3370.1640.4770.4880.4570.9300.1320.7730.7270.2900.5670.3020.6080.0360.664Table S19. Pearson R values (n = 6) for MWCNT, day 1Table S20. P values (n = 6) for MWCNT, day 1

21. 21(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.710.61-0.510.44-0.210.480.03-0.45-0.450.12-0.54-0.10-0.11-0.010.40(B) Multi Mac0.711.000.41-0.250.370.110.200.22-0.19-0.61-0.19-0.49-0.39-0.620.380.26(C) Neutrophil0.610.411.00-0.350.270.100.710.33-0.75-0.020.24-0.450.14-0.22-0.170.06(D) SAA-3-0.51-0.25-0.351.000.160.400.270.190.260.29-0.760.12-0.47-0.32-0.25-0.40(E) TNF-a0.440.370.270.161.000.690.620.790.30-0.710.090.300.220.150.400.73(F) IL-1b-0.210.110.100.400.691.000.310.960.49-0.490.080.600.32-0.020.590.44(G) IL-1a0.480.200.710.270.620.311.000.44-0.470.01-0.17-0.29-0.06-0.14-0.370.06(H) IL-60.030.220.330.190.790.960.441.000.34-0.580.240.520.430.050.580.58(I) HSP70-0.45-0.19-0.750.260.300.49-0.470.341.00-0.510.110.830.270.370.680.50(J) HO-1-0.45-0.61-0.020.29-0.71-0.490.01-0.58-0.511.00-0.32-0.34-0.27-0.12-0.85-0.88(K) SOD10.12-0.190.24-0.760.090.08-0.170.240.11-0.321.000.490.930.720.400.62(L) SOD2-0.54-0.49-0.450.120.300.60-0.290.520.83-0.340.491.000.710.660.580.55(M) GSH-0.10-0.390.14-0.470.220.32-0.060.430.27-0.270.930.711.000.810.390.62(N) RAD51-0.11-0.62-0.22-0.320.15-0.02-0.140.050.37-0.120.720.660.811.000.100.54(O) Ligase IV-0.010.38-0.17-0.250.400.59-0.370.580.68-0.850.400.580.390.101.000.71(P) OGG10.400.260.06-0.400.730.440.060.580.50-0.880.620.550.620.540.711.00(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.1130.2030.3060.3810.6920.3390.9610.3690.3700.8180.2730.8490.8400.9840.427(B) Multi Mac0.1130.4190.6330.4690.8290.7020.6780.7150.2000.7240.3260.4430.1930.4590.623(C) Neutrophil0.2030.4190.5000.6050.8440.1160.5260.0890.9670.6500.3760.7880.6770.7400.909(D) SAA-30.3060.6330.5000.7580.4370.6110.7170.6170.5780.0820.8260.3510.5430.6350.434(E) TNF-a0.3810.4690.6050.7580.1300.1930.0640.5600.1110.8670.5650.6730.7800.4300.097(F) IL-1b0.6920.8290.8440.4370.1300.5540.0020.3200.3210.8870.2090.5400.9740.2160.379(G) IL-1a0.3390.7020.1160.6110.1930.5540.3800.3490.9790.7440.5840.9040.7970.4690.903(H) IL-60.9610.6780.5260.7170.0640.0020.3800.5040.2310.6480.2910.3950.9220.2230.233(I) HSP700.3690.7150.0890.6170.5600.3200.3490.5040.2960.8430.0420.5990.4670.1360.309(J) HO-10.3700.2000.9670.5780.1110.3210.9790.2310.2960.5380.5070.6090.8260.0330.020(K) SOD10.8180.7240.6500.0820.8670.8870.7440.6480.8430.5380.3290.0070.1050.4270.187(L) SOD20.2730.3260.3760.8260.5650.2090.5840.2910.0420.5070.3290.1120.1510.2280.263(M) GSH0.8490.4430.7880.3510.6730.5400.9040.3950.5990.6090.0070.1120.0520.4410.187(N) RAD510.8400.1930.6770.5430.7800.9740.7970.9220.4670.8260.1050.1510.0520.8480.264(O) Ligase IV0.9840.4590.7400.6350.4300.2160.4690.2230.1360.0330.4270.2280.4410.8480.114(P) OGG10.4270.6230.9090.4340.0970.3790.9030.2330.3090.0200.1870.2630.1870.2640.114Table S21. Pearson R values (n = 6) for MWCNT, day 7Table S22. P values (n = 6) for MWCNT, day 7

22. 22(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.790.640.640.21-0.590.34-0.570.250.950.690.860.800.820.280.45(B) Multi Mac0.791.000.790.630.44-0.600.72-0.21-0.250.650.340.700.420.37-0.24-0.07(C) Neutrophil0.640.791.000.930.84-0.050.90-0.26-0.510.52-0.060.500.070.48-0.21-0.33(D) SAA-30.640.630.931.000.740.150.81-0.53-0.440.620.040.560.140.670.13-0.26(E) TNF-a0.210.440.840.741.000.260.800.15-0.610.06-0.480.12-0.420.13-0.47-0.52(F) IL-1b-0.59-0.60-0.050.150.261.000.10-0.09-0.48-0.47-0.69-0.56-0.66-0.110.16-0.55(G) IL-1a0.340.720.900.810.800.101.00-0.12-0.810.24-0.290.29-0.200.15-0.36-0.68(H) IL-6-0.57-0.21-0.26-0.530.15-0.09-0.121.00-0.10-0.74-0.52-0.50-0.64-0.84-0.85-0.24(I) HSP700.25-0.25-0.51-0.44-0.61-0.48-0.81-0.101.000.300.690.240.630.300.440.97(J) HO-10.950.650.520.620.06-0.470.24-0.740.301.000.790.910.840.900.530.48(K) SOD10.690.34-0.060.04-0.48-0.69-0.29-0.520.690.791.000.790.920.590.580.77(L) SOD20.860.700.500.560.12-0.560.29-0.500.240.910.791.000.690.690.340.39(M) GSH0.800.420.070.14-0.42-0.66-0.20-0.640.630.840.920.691.000.720.580.76(N) RAD510.820.370.480.670.13-0.110.15-0.840.300.900.590.690.721.000.690.47(O) Ligase IV0.28-0.24-0.210.13-0.470.16-0.36-0.850.440.530.580.340.580.691.000.48(P) OGG10.45-0.07-0.33-0.26-0.52-0.55-0.68-0.240.970.480.770.390.760.470.481.00(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0620.1740.1740.6930.2200.5080.2420.6400.0030.1280.0280.0570.0470.5940.373(B) Multi Mac0.0620.0630.1790.3860.2100.1090.6930.6290.1590.5060.1200.4090.4700.6500.896(C) Neutrophil0.1740.0630.0070.0340.9320.0150.6210.3030.2930.9080.3160.9020.3360.6960.527(D) SAA-30.1740.1790.0070.0930.7840.0520.2800.3800.1860.9430.2520.7880.1440.8020.616(E) TNF-a0.6930.3860.0340.0930.6250.0570.7690.2030.9090.3380.8210.4110.8110.3420.295(F) IL-1b0.2200.2100.9320.7840.6250.8500.8670.3370.3490.1310.2470.1550.8340.7610.256(G) IL-1a0.5080.1090.0150.0520.0570.8500.8140.0490.6450.5750.5820.6980.7730.4840.139(H) IL-60.2420.6930.6210.2800.7690.8670.8140.8520.0910.2880.3080.1680.0360.0310.650(I) HSP700.6400.6290.3030.3800.2030.3370.0490.8520.5680.1320.6470.1820.5640.3780.001(J) HO-10.0030.1590.2930.1860.9090.3490.6450.0910.5680.0600.0120.0340.0150.2780.332(K) SOD10.1280.5060.9080.9430.3380.1310.5750.2880.1320.0600.0600.0100.2140.2230.073(L) SOD20.0280.1200.3160.2520.8210.2470.5820.3080.6470.0120.0600.1270.1320.5040.449(M) GSH0.0570.4090.9020.7880.4110.1550.6980.1680.1820.0340.0100.1270.1080.2240.078(N) RAD510.0470.4700.3360.1440.8110.8340.7730.0360.5640.0150.2140.1320.1080.1320.344(O) Ligase IV0.5940.6500.6960.8020.3420.7610.4840.0310.3780.2780.2230.5040.2240.1320.331(P) OGG10.3730.8960.5270.6160.2950.2560.1390.6500.0010.3320.0730.4490.0780.3440.331Table S23. Pearson R values (n = 6) for MWCNT, day 28Table S24. P values (n = 6) for MWCNT, day 28

23. (A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac1.000.76-0.31-0.49-0.250.050.25-0.320.16-0.340.16-0.240.28-0.790.49-0.56(B) Multi Mac0.761.00-0.150.01-0.21-0.380.21-0.110.18-0.050.070.350.72-0.950.29-0.13(C) Neutrophil-0.31-0.151.000.740.790.30-0.180.110.210.47-0.620.110.120.81-0.590.12(D) SAA-3-0.490.010.741.000.88-0.130.08-0.080.000.49-0.450.820.280.56-0.660.74(E) TNF-a-0.25-0.210.790.881.000.560.32-0.350.150.40-0.680.12-0.300.82-0.840.44(F) IL-1b0.05-0.380.30-0.130.561.000.52-0.110.530.38-0.69-0.25-0.760.62-0.61-0.45(G) IL-1a0.250.21-0.180.080.320.521.00-0.300.510.40-0.530.41-0.460.18-0.510.15(H) IL-6-0.32-0.110.11-0.08-0.35-0.11-0.301.000.560.59-0.280.350.240.72-0.34-0.43(I) HSP700.160.180.210.000.150.530.510.561.000.84-0.820.45-0.100.74-0.66-0.45(J) HO-1-0.34-0.050.470.490.400.380.400.590.841.00-0.900.70-0.080.97-0.960.06(K) SOD10.160.07-0.62-0.45-0.68-0.69-0.53-0.28-0.82-0.901.00-0.450.27-0.940.900.05(L) SOD2-0.240.350.110.820.12-0.250.410.350.450.70-0.451.000.310.63-0.870.70(M) GSH0.280.720.120.28-0.30-0.76-0.460.24-0.10-0.080.270.311.00-0.320.410.02(N) RAD51-0.79-0.950.810.560.820.620.180.720.740.97-0.940.63-0.321.00-0.910.08(O) Ligase IV0.490.29-0.59-0.66-0.84-0.61-0.51-0.34-0.66-0.960.90-0.870.41-0.911.00-0.33(P) OGG1-0.56-0.130.120.740.44-0.450.15-0.43-0.450.060.050.700.020.08-0.331.0023(A) Total Mac(B) Multi Mac(C) Neutrophil(D) SAA-3(E) TNF-a(F) IL-1b(G) IL-1a(H) IL-6(I) HSP70(J) HO-1(K) SOD1(L) SOD2(M) GSH(N) RAD51(O) Ligase IV(P) OGG1(A) Total Mac0.0790.5460.3970.6280.9300.6380.5430.7680.5160.7680.6520.5840.2080.4000.330(B) Multi Mac0.0790.7800.9840.6900.4560.6960.8410.7270.9260.8900.4940.1090.0470.6400.832(C) Neutrophil0.5460.7800.1530.0600.5650.7300.8320.6920.3460.1900.8400.8210.1880.2940.850(D) SAA-30.3970.9840.1530.0520.8350.9020.8930.9950.3990.4490.0880.6440.4350.2290.150(E) TNF-a0.6280.6900.0600.0520.2480.5310.5000.7750.4330.1390.8220.5620.1760.0760.462(F) IL-1b0.9300.4560.5650.8350.2480.2900.8410.2800.4590.1310.6360.0810.3770.2700.447(G) IL-1a0.6380.6960.7300.9020.5310.2900.5680.3030.4310.2830.4140.3610.8190.3850.811(H) IL-60.5430.8410.8320.8930.5000.8410.5680.2500.2130.5870.4920.6460.2830.5740.468(I) HSP700.7680.7270.6920.9950.7750.2800.3030.2500.0380.0470.3670.8500.2620.2250.448(J) HO-10.5160.9260.3460.3990.4330.4590.4310.2130.0380.0160.1190.8760.0330.0100.929(K) SOD10.7680.8900.1900.4490.1390.1310.2830.5870.0470.0160.3740.6020.0560.0350.938(L) SOD20.6520.4940.8400.0880.8220.6360.4140.4920.3670.1190.3740.5500.3750.0560.191(M) GSH0.5840.1090.8210.6440.5620.0810.3610.6460.8500.8760.6020.5500.6790.4960.970(N) RAD510.2080.0470.1880.4350.1760.3770.8190.2830.2620.0330.0560.3750.6790.0890.920(O) Ligase IV0.4000.6400.2940.2290.0760.2700.3850.5740.2250.0100.0350.0560.4960.0890.582(P) OGG10.3300.8320.8500.1500.4620.4470.8110.4680.4480.9290.9380.1910.9700.9200.582Table S25. Pearson R values (n = 6) for MWCNT, day 84Table S26. P values (n = 6) for MWCNT, day 84