Table S1. Proteins identifed by LC-MS/MS for global sex difference, global minocycline effect and the interaction between sex and minocycline treatment Global minocycline Protein information ANOVA Global sex difference Interaction effect difference ((MalesH + ((MalesHM + Sex MalesHM) - FemalesHM) - difference x uniProt Identifier uniProtKB Protein names Gene names q-values p-values p-values p-values (FemalesH + (MalesH + minocycline FemalesHM)) FemalesH)) difference PYR1_MOUSE B2RQC6 CAD protein [Includes: Glutamine- dependent carbamoyl-phosphate synthase (EC 6.3.5.5); Aspartate Cad 7,94E-03 0,82 3,09E-04 0,46 2,47E-02 0,72 6,84E-02 carbamoyltransferase (EC 2.1.3.2); Dihydroorotase (EC 3.5.2.3)] FIBA_MOUSE E9PV24 Fibrinogen alpha chain [Cleaved into: Fga 2,55E-02 0,19 5,83E-03 0,11 7,91E-02 0,32 1,61E-02 Fibrinopeptide A; Fibrinogen alpha chain] KNG1_MOUSE O08677 Kininogen-1 [Cleaved into: Kininogen-1 heavy chain; Bradykinin; Kininogen-1 light Kng1 Kng 1,13E-02 0,14 2,01E-01 0,40 9,17E-04 0,57 1,22E-02 chain] IMPA1_MOUSE O55023 Inositol monophosphatase 1 (IMP 1) (IMPase 1) (EC 3.1.3.25) (D-galactose 1- phosphate phosphatase) (EC 3.1.3.94) Impa1 1,56E-03 0,05 1,31E-02 -0,07 2,24E-03 -0,15 1,28E-03 (Inositol-1(or 4)-monophosphatase 1) (Lithium-sensitive myo-inositol monophosphatase A1) CO3_MOUSE P01027 Complement C3 (HSE-MSF) [Cleaved into: Complement C3 beta chain; C3-beta-c (C3bc); Complement C3 alpha chain; C3a anaphylatoxin; Acylation stimulating protein (ASP) (C3adesArg); Complement C3b alpha' chain; Complement C3c alpha' C3 1,67E-02 0,01 8,71E-01 0,20 1,62E-03 0,33 8,39E-03 chain fragment 1; Complement C3dg fragment; Complement C3g fragment; Complement C3d fragment; Complement C3f fragment; Complement C3c alpha' chain fragment 2] CO4B_MOUSE P01029 Complement C4-B [Cleaved into: Complement C4 beta chain; Complement C4b C4 1,91E-02 0,00 9,88E-01 0,02 6,57E-01 0,39 6,21E-04 C4 alpha chain; C4a anaphylatoxin; Complement C4 gamma chain] HBA_MOUSE P01942 Hemoglobin subunit alpha (Alpha-globin) Hba Hba-a1 1,73E-03 0,79 9,14E-06 0,28 4,77E-02 0,08 7,55E-01 (Hemoglobin alpha chain) HBB1_MOUSE P02088 Hemoglobin subunit beta-1 (Beta-1- globin) (Hemoglobin beta-1 chain) Hbb-b1 1,07E-02 0,63 9,49E-05 0,28 4,15E-02 0,11 6,80E-01 (Hemoglobin beta-major chain) B3AT_MOUSE P04919 Band 3 anion transport protein (Anion exchange protein 1) (AE 1) (Anion Slc4a1 Ae1 2,55E-02 0,38 1,68E-04 0,10 2,21E-01 0,07 6,76E-01 exchanger 1) (MEB3) (Solute carrier family 4 member 1) (CD antigen CD233) APOA4_MOUSE P06728 Apolipoprotein A-IV (Apo-AIV) (ApoA-IV) Apoa4 6,43E-03 0,18 1,35E-02 0,26 1,08E-03 0,35 1,87E-02 (Apolipoprotein A4) SPRC_MOUSE P07214 SPARC (Basement-membrane protein 40) (BM-40) (Osteonectin) (ON) (Secreted Sparc 4,34E-02 0,04 4,33E-01 0,01 9,07E-01 0,39 1,21E-03 protein acidic and rich in cysteine) ALBU_MOUSE P07724 Serum albumin Alb Alb-1 Alb1 8,72E-03 0,08 5,04E-01 0,58 1,50E-04 0,55 3,73E-02 SPA3K_MOUSE P07759 Serine protease inhibitor A3K (Serpin A3K) Serpina3k Mcm2 Spi2 1,69E-06 0,93 2,27E-08 0,44 4,76E-04 0,77 1,55E-03 (Contrapsin) (SPI-2) NFM_MOUSE P08553 Neurofilament medium polypeptide (NF- M) (160 kDa neurofilament protein) Nefm Nef3 Nfm 3,67E-02 0,18 1,73E-04 0,01 7,74E-01 -0,04 5,96E-01 (Neurofilament 3) (Neurofilament triplet M protein) HSPB1_MOUSE P14602 Heat shock protein beta-1 (HspB1) (Growth-related 25 kDa protein) (Heat Hspb1 Hsp25 Hsp27 2,03E-03 -0,05 4,48E-01 0,08 2,25E-01 0,61 8,60E-05 shock 25 kDa protein) (HSP 25) (Heat shock 27 kDa protein) (HSP 27) (p25) GRP78_MOUSE P20029 78 kDa glucose-regulated protein (GRP-78) (Heat shock 70 kDa protein 5) Hspa5 Grp78 7,58E-03 0,00 1,00E+00 0,04 1,06E-01 0,22 3,36E-04 (Immunoglobulin heavy chain-binding protein) (BiP) HEXB_MOUSE P20060 Beta-hexosaminidase subunit beta (EC 3.2.1.52) (Beta-N-acetylhexosaminidase subunit beta) (Hexosaminidase subunit B) Hexb 3,15E-03 -0,09 2,69E-02 0,06 1,56E-01 0,32 3,56E-04 (N-acetyl-beta-glucosaminidase subunit beta) VTDB_MOUSE P21614 Vitamin D-binding protein (DBP) (VDB) (Gc- globulin) (Group-specific component) Gc 1,91E-02 0,28 6,91E-02 0,42 8,59E-03 0,84 8,30E-03 PENK_MOUSE P22005 Proenkephalin-A [Cleaved into: Synenkephalin; Met-enkephalin (Opioid growth factor) (OGF); PENK(114-133); Penk Penk1 1,85E-02 0,25 9,68E-05 -0,04 4,13E-01 0,08 4,13E-01 PENK(143-184); Met-enkephalin-Arg-Ser- Leu; Leu-enkephalin; PENK(238-259); Met- enkephalin-Arg-Phe] A1AT2_MOUSE P22599 Alpha-1-antitrypsin 1-2 (AAT) (Alpha-1 protease inhibitor 2) (Alpha-1- Serpina1b Aat2 Dom2 antiproteinase) (Serine protease inhibitor 1- 4,34E-02 0,25 9,52E-02 0,49 2,31E-03 0,55 6,80E-02 Spi1-2 2) (Serine protease inhibitor A1b) (Serpin A1b) RS2_MOUSE P25444 40S ribosomal protein S2 (40S ribosomal Rps2 Llrep3 Rps4 1,93E-02 -0,02 5,44E-01 0,00 9,92E-01 0,21 6,72E-04 protein S4) (Protein LLRep3) EZRI_MOUSE P26040 Ezrin (Cytovillin) (Villin-2) (p81) Ezr Vil2 1,56E-03 -0,06 3,60E-02 0,07 2,31E-02 0,25 2,37E-04 PDIA3_MOUSE P27773 Protein disulfide-isomerase A3 (EC 5.3.4.1) (58 kDa glucose-regulated protein) (58 kDa microsomal protein) (p58) (Disulfide isomerase ER-60) (Endoplasmic reticulum Pdia3 Erp Erp60 Grp58 1,73E-02 -0,01 6,90E-01 0,04 1,24E-01 0,18 8,48E-04 resident protein 57) (ER protein 57) (ERp57) (Endoplasmic reticulum resident protein 60) (ER protein 60) (ERp60) SEPT4_MOUSE P28661 Septin-4 (Brain protein H5) (Peanut-like Sept4 Pnutl2 2,17E-02 -0,01 6,00E-01 -0,04 9,80E-02 -0,17 1,37E-03 protein 2) FETUA_MOUSE P29699 Alpha-2-HS-glycoprotein (Countertrypin) Ahsg Fetua 1,56E-03 0,08 4,66E-01 0,48 4,09E-04 0,87 1,09E-03 (Fetuin-A) VTNC_MOUSE P29788 Vitronectin (VN) (S-protein) (Serum- Vtn 1,56E-03 0,17 4,89E-05 0,15 1,68E-04 0,16 1,56E-02 spreading factor) APOC1_MOUSE P34928 Apolipoprotein C-I (Apo-CI) (ApoC-I) (Apolipoprotein C1) [Cleaved into: Apoc1 6,27E-04 0,75 5,86E-06 0,36 8,40E-03 0,46 7,34E-02 Truncated apolipoprotein C-I] COIA1_MOUSE P39061 Collagen alpha-1(XVIII) chain [Cleaved into: Col18a1 8,03E-03 0,25 2,01E-04 0,14 2,10E-02 0,16 1,52E-01 Endostatin] EF2_MOUSE P58252 Elongation factor 2 (EF-2) Eef2 1,93E-02 0,00 9,25E-01 0,03 2,48E-01 0,19 8,24E-04 RS8_MOUSE P62242 40S ribosomal protein S8 Rps8 1,56E-03 -0,03 2,77E-01 0,05 1,24E-01 0,29 8,19E-05 RS12_MOUSE P63323 40S ribosomal protein S12 Rps12 4,55E-02 -0,04 3,36E-01 0,06 9,10E-02 0,24 3,46E-03 APOA1_MOUSE Q00623 Apolipoprotein A-I (Apo-AI) (ApoA-I) (Apolipoprotein A1) [Cleaved into: Apoa1 8,60E-04 0,54 2,26E-05 0,32 3,74E-03 0,39 6,11E-02 Proapolipoprotein A-I (ProapoA-I); Truncated apolipoprotein A-I] A1AT4_MOUSE Q00897 Alpha-1-antitrypsin 1-4 (Alpha-1 protease inhibitor 4) (Serine protease inhibitor 1-4) Serpina1d Dom4 Spi1-4 1,24E-02 0,25 3,87E-02 0,43 1,05E-03 0,52 3,15E-02 (Serine protease inhibitor A1d) (Serpin A1d) A1AT5_MOUSE Q00898 Alpha-1-antitrypsin 1-5 (Alpha-1 protease inhibitor 5) (Serine protease inhibitor 1-5) Serpina1e Dom5 Spi1-5 1,15E-07 1,87 1,53E-10 0,56 1,85E-03 0,92 8,12E-03 (Serine protease inhibitor A1e) (Serpin A1e)

CLUS_MOUSE Q06890 Clusterin (Apolipoprotein J) (Apo-J) (Clustrin) (Sulfated glycoprotein 2) (SGP-2) Clu Apoj Msgp-2 1,76E-04 0,12 2,94E-03 0,10 1,22E-02 0,39 3,43E-05 [Cleaved into: Clusterin beta chain; Clusterin alpha chain] CALB2_MOUSE Q08331 Calretinin (CR) Calb2 2,16E-02 0,16 7,46E-04 -0,03 4,84E-01 -0,18 3,38E-02 PADI2_MOUSE Q08642 Protein-arginine deiminase type-2 (EC 3.5.3.15) (Peptidylarginine deiminase II) Padi2 Pad2 Pdi Pdi2 4,20E-02 0,02 6,48E-01 -0,01 7,48E-01 -0,30 1,34E-03 (Protein-arginine deiminase type II) MYO1D_MOUSE Q5SYD0 Unconventional myosin-Id Myo1d 2,55E-02 0,03 1,18E-01 -0,03 5,74E-02 -0,10 3,46E-03 CD166_MOUSE Q61490 CD166 antigen (Activated leukocyte cell adhesion molecule) (BEN) (Protein DM- Alcam 4,20E-02 -0,09 1,35E-03 -0,03 1,75E-01 -0,09 7,62E-02 GRASP) (CD antigen CD166) GDIB_MOUSE Q61598 Rab GDP dissociation inhibitor beta (Rab GDI beta) (GDI-3) (Guanosine diphosphate Gdi2 Gdi3 4,89E-02 0,10 3,69E-04 -0,03 2,24E-01 -0,02 5,99E-01 dissociation inhibitor 2) (GDI-2)

HPT_MOUSE Q61646 Haptoglobin (Zonulin) [Cleaved into: Haptoglobin alpha chain; Haptoglobin beta Hp 2,74E-05 0,84 9,02E-06 0,47 3,61E-03 1,34 1,48E-04 chain] PZP_MOUSE Q61838 Pregnancy zone protein (Alpha-2- macroglobulin) (Alpha-2-M) [Cleaved into: Pzp A2m 1,56E-03 0,33 6,61E-05 0,23 2,29E-03 0,19 1,55E-01 Alpha-2-macroglobulin 165 kDa subunit; Alpha-2-macroglobulin 35 kDa subunit] CSPG2_MOUSE Q62059 Versican core protein (Chondroitin sulfate proteoglycan core protein 2) (Chondroitin Vcan Cspg2 8,60E-04 -0,02 1,01E-01 -0,05 3,52E-04 -0,10 5,19E-04 sulfate proteoglycan 2) (Large fibroblast proteoglycan) (PG-M) DDX3X_MOUSE Q62167 ATP-dependent RNA helicase DDX3X (EC 3.6.4.13) (D1Pas1-related sequence 2) Ddx3x D1Pas1-rs2 Ddx3 (DEAD box RNA helicase DEAD3) 6,27E-04 -0,29 8,08E-07 0,02 7,15E-01 0,06 4,97E-01 Dead3 Erh (mDEAD3) (DEAD box protein 3, X- chromosomal) (Embryonic RNA helicase) IF4G1_MOUSE Q6NZJ6 Eukaryotic translation initiation factor 4 gamma 1 (eIF-4-gamma 1) (eIF-4G 1) (eIF- Eif4g1 3,61E-03 0,00 8,57E-01 0,02 2,00E-01 0,15 1,45E-04 4G1) VAT1L_MOUSE Q80TB8 Synaptic vesicle membrane protein VAT-1 Vat1l Kiaa1576 3,58E-02 0,16 3,07E-03 0,04 4,12E-01 0,24 1,87E-02 homolog-like (EC 1.-.-.-) FIBB_MOUSE Q8K0E8 Fibrinogen beta chain [Cleaved into: Fgb 1,56E-03 0,28 1,25E-03 0,21 9,70E-03 0,52 2,16E-03 Fibrinopeptide B; Fibrinogen beta chain] SPA3N_MOUSE Q91WP6 Serine protease inhibitor A3N (Serpin A3N) Serpina3n Spi2 1,25E-02 -0,09 4,85E-01 0,22 9,27E-02 0,99 7,31E-04

HEMO_MOUSE Q91X72 Hemopexin Hpx Hpxn 4,02E-06 0,45 5,23E-06 0,39 2,68E-05 0,69 1,25E-04 TRFE_MOUSE Q921I1 Serotransferrin (Transferrin) (Beta-1 metal- Tf Trf 2,09E-03 0,12 1,73E-01 0,33 1,15E-03 0,66 1,17E-03 binding globulin) (Siderophilin) PSIP1_MOUSE Q99JF8 PC4 and SFRS1-interacting protein (Lens epithelium-derived growth factor) Psip1 Ledgf 1,91E-02 -0,10 1,62E-04 -0,03 2,33E-01 -0,05 2,70E-01 (mLEDGF) PBDC1_MOUSE Q9D0B6 Protein PBDC1 (Polysaccharide biosynthesis domain-containing protein 1) Pbdc1 1,14E-02 -0,16 5,12E-05 -0,03 3,65E-01 0,05 4,48E-01

GATM_MOUSE Q9D964 Glycine amidinotransferase, mitochondrial (EC 2.1.4.1) (L-arginine:glycine Gatm 1,73E-02 -0,12 3,35E-02 -0,07 2,16E-01 0,41 1,23E-03 amidinotransferase) (Transamidinase) SNP29_MOUSE Q9ERB0 Synaptosomal-associated protein 29 (SNAP-29) (Golgi SNARE of 32 kDa) (Gs32) (Soluble 29 kDa NSF attachment protein) Snap29 1,73E-02 0,29 1,02E-03 0,18 2,24E-02 0,41 1,07E-02 (Vesicle-membrane fusion protein SNAP- 29) Table S2. Proteins identifed by LC-MS/MS for sex difference in vehicle and minocycline effects in males and females Sex difference in Minocycline effect in Minocycline effect in Protein information ANOVA vehicle males females (MalesH- (MalesHM- (FemalesHM- uniProt Identifier uniProtKB Protein names Gene names q-values p-value p-values p-values FemaleH) MalesH) FemalesH) PYR1_MOUSE B2RQC6 CAD protein [Includes: Glutamine- dependent carbamoyl-phosphate synthase (EC 6.3.5.5); Aspartate Cad 7,94E-03 0,45 1,02E-01 0,82 5,90E-03 0,09 7,26E-01 carbamoyltransferase (EC 2.1.3.2); Dihydroorotase (EC 3.5.2.3)] FIBA_MOUSE E9PV24 Fibrinogen alpha chain [Cleaved into: Fga 2,55E-02 0,03 7,50E-01 0,27 4,85E-03 -0,05 5,88E-01 Fibrinopeptide A; Fibrinogen alpha chain] KNG1_MOUSE O08677 Kininogen-1 [Cleaved into: Kininogen-1 heavy chain; Bradykinin; Kininogen-1 light Kng1 Kng 1,13E-02 -0,15 3,23E-01 0,69 1,38E-04 0,12 4,33E-01 chain] IMPA1_MOUSE O55023 Inositol monophosphatase 1 (IMP 1) (IMPase 1) (EC 3.1.3.25) (D-galactose 1- phosphate phosphatase) (EC 3.1.3.94) Impa1 1,56E-03 0,13 1,86E-04 -0,15 5,19E-05 0,00 8,67E-01 (Inositol-1(or 4)-monophosphatase 1) (Lithium-sensitive myo-inositol monophosphatase A1) CO3_MOUSE P01027 Complement C3 (HSE-MSF) [Cleaved into: Complement C3 beta chain; C3-beta-c (C3bc); Complement C3 alpha chain; C3a anaphylatoxin; Acylation stimulating protein (ASP) (C3adesArg); Complement C3b alpha' chain; Complement C3c alpha' C3 1,67E-02 -0,15 6,52E-02 0,37 1,57E-04 0,04 6,17E-01 chain fragment 1; Complement C3dg fragment; Complement C3g fragment; Complement C3d fragment; Complement C3f fragment; Complement C3c alpha' chain fragment 2] CO4B_MOUSE P01029 Complement C4-B [Cleaved into: Complement C4 beta chain; Complement C4b C4 1,91E-02 -0,20 9,32E-03 0,22 4,66E-03 -0,17 1,92E-02 C4 alpha chain; C4a anaphylatoxin; Complement C4 gamma chain] HBA_MOUSE P01942 Hemoglobin subunit alpha (Alpha-globin) Hba Hba-a1 1,73E-03 0,75 8,02E-04 0,33 1,02E-01 0,24 2,19E-01 (Hemoglobin alpha chain) HBB1_MOUSE P02088 Hemoglobin subunit beta-1 (Beta-1- globin) (Hemoglobin beta-1 chain) Hbb-b1 1,07E-02 0,58 5,15E-03 0,34 8,12E-02 0,23 2,28E-01 (Hemoglobin beta-major chain) B3AT_MOUSE P04919 Band 3 anion transport protein (Anion exchange protein 1) (AE 1) (Anion Slc4a1 Ae1 2,55E-02 0,34 7,69E-03 0,14 2,47E-01 0,07 5,60E-01 exchanger 1) (MEB3) (Solute carrier family 4 member 1) (CD antigen CD233) APOA4_MOUSE P06728 Apolipoprotein A-IV (Apo-AIV) (ApoA-IV) Apoa4 6,43E-03 0,01 9,17E-01 0,43 2,15E-04 0,08 3,85E-01 (Apolipoprotein A4) SPRC_MOUSE P07214 SPARC (Basement-membrane protein 40) (BM-40) (Osteonectin) (ON) (Secreted Sparc 4,34E-02 -0,15 4,23E-02 0,20 1,14E-02 -0,19 1,61E-02 protein acidic and rich in cysteine) ALBU_MOUSE P07724 Serum albumin Alb Alb-1 Alb1 8,72E-03 -0,19 2,86E-01 0,86 9,19E-05 0,30 1,01E-01 SPA3K_MOUSE P07759 Serine protease inhibitor A3K (Serpin A3K) Serpina3k Mcm2 Spi2 1,69E-06 0,55 1,47E-03 0,82 2,04E-05 0,05 7,24E-01 (Contrapsin) (SPI-2) NFM_MOUSE P08553 Neurofilament medium polypeptide (NF- M) (160 kDa neurofilament protein) Nefm Nef3 Nfm 3,67E-02 0,20 1,65E-03 -0,01 8,62E-01 0,03 5,64E-01 (Neurofilament 3) (Neurofilament triplet M protein) HSPB1_MOUSE P14602 Heat shock protein beta-1 (HspB1) (Growth-related 25 kDa protein) (Heat Hspb1 Hsp25 Hsp27 2,03E-03 -0,36 6,81E-04 0,39 3,09E-04 -0,23 1,79E-02 shock 25 kDa protein) (HSP 25) (Heat shock 27 kDa protein) (HSP 27) (p25) GRP78_MOUSE P20029 78 kDa glucose-regulated protein (GRP-78) (Heat shock 70 kDa protein 5) Hspa5 Grp78 7,58E-03 -0,11 6,29E-03 0,16 3,94E-04 -0,07 7,83E-02 (Immunoglobulin heavy chain-binding protein) (BiP) HEXB_MOUSE P20060 Beta-hexosaminidase subunit beta (EC 3.2.1.52) (Beta-N-acetylhexosaminidase subunit beta) (Hexosaminidase subunit B) Hexb 3,15E-03 -0,25 1,30E-04 0,22 5,87E-04 -0,11 6,02E-02 (N-acetyl-beta-glucosaminidase subunit beta) VTDB_MOUSE P21614 Vitamin D-binding protein (DBP) (VDB) (Gc- globulin) (Group-specific component) Gc 1,91E-02 -0,14 4,84E-01 0,84 5,17E-04 0,00 9,91E-01 PENK_MOUSE P22005 Proenkephalin-A [Cleaved into: Synenkephalin; Met-enkephalin (Opioid growth factor) (OGF); PENK(114-133); Penk Penk1 1,85E-02 0,20 1,01E-02 0,00 9,99E-01 -0,08 2,51E-01 PENK(143-184); Met-enkephalin-Arg-Ser- Leu; Leu-enkephalin; PENK(238-259); Met- enkephalin-Arg-Phe] A1AT2_MOUSE P22599 Alpha-1-antitrypsin 1-2 (AAT) (Alpha-1 protease inhibitor 2) (Alpha-1- Serpina1b Aat2 Dom2 antiproteinase) (Serine protease inhibitor 1- 4,34E-02 -0,03 9,01E-01 0,77 1,04E-03 0,22 2,83E-01 Spi1-2 2) (Serine protease inhibitor A1b) (Serpin A1b) RS2_MOUSE P25444 40S ribosomal protein S2 (40S ribosomal Rps2 Llrep3 Rps4 1,93E-02 -0,12 3,76E-03 0,10 9,91E-03 -0,10 1,02E-02 protein S4) (Protein LLRep3) EZRI_MOUSE P26040 Ezrin (Cytovillin) (Villin-2) (p81) Ezr Vil2 1,56E-03 -0,19 1,23E-04 0,20 8,71E-05 -0,06 1,72E-01 PDIA3_MOUSE P27773 Protein disulfide-isomerase A3 (EC 5.3.4.1) (58 kDa glucose-regulated protein) (58 kDa microsomal protein) (p58) (Disulfide isomerase ER-60) (Endoplasmic reticulum Pdia3 Erp Erp60 Grp58 1,73E-02 -0,10 6,21E-03 0,13 8,72E-04 -0,05 1,18E-01 resident protein 57) (ER protein 57) (ERp57) (Endoplasmic reticulum resident protein 60) (ER protein 60) (ERp60) SEPT4_MOUSE P28661 Septin-4 (Brain protein H5) (Peanut-like Sept4 Pnutl2 2,17E-02 0,07 3,59E-02 -0,12 9,89E-04 0,04 1,77E-01 protein 2) FETUA_MOUSE P29699 Alpha-2-HS-glycoprotein (Countertrypin) Ahsg Fetua 1,56E-03 -0,35 4,21E-02 0,92 1,44E-05 0,05 7,71E-01 (Fetuin-A) VTNC_MOUSE P29788 Vitronectin (VN) (S-protein) (Serum- Vtn 1,56E-03 0,09 3,58E-02 0,23 8,62E-05 0,07 9,59E-02 spreading factor) APOC1_MOUSE P34928 Apolipoprotein C-I (Apo-CI) (ApoC-I) (Apolipoprotein C1) [Cleaved into: Apoc1 6,27E-04 0,51 7,49E-03 0,59 2,82E-03 0,13 4,73E-01 Truncated apolipoprotein C-I] COIA1_MOUSE P39061 Collagen alpha-1(XVIII) chain [Cleaved into: Col18a1 8,03E-03 0,16 4,35E-02 0,22 1,05E-02 0,05 4,81E-01 Endostatin] EF2_MOUSE P58252 Elongation factor 2 (EF-2) Eef2 1,93E-02 -0,09 1,34E-02 0,12 1,70E-03 -0,07 6,67E-02 RS8_MOUSE P62242 40S ribosomal protein S8 Rps8 1,56E-03 -0,18 3,73E-04 0,19 1,66E-04 -0,10 2,95E-02 RS12_MOUSE P63323 40S ribosomal protein S12 Rps12 4,55E-02 -0,16 6,45E-03 0,18 1,79E-03 -0,06 2,90E-01 APOA1_MOUSE Q00623 Apolipoprotein A-I (Apo-AI) (ApoA-I) (Apolipoprotein A1) [Cleaved into: Apoa1 8,60E-04 0,35 2,22E-02 0,52 1,34E-03 0,13 3,70E-01 Proapolipoprotein A-I (ProapoA-I); Truncated apolipoprotein A-I] A1AT4_MOUSE Q00897 Alpha-1-antitrypsin 1-4 (Alpha-1 protease inhibitor 4) (Serine protease inhibitor 1-4) Serpina1d Dom4 Spi1-4 1,24E-02 -0,01 9,45E-01 0,69 3,15E-04 0,17 2,96E-01 (Serine protease inhibitor A1d) (Serpin A1d) A1AT5_MOUSE Q00898 Alpha-1-antitrypsin 1-5 (Alpha-1 protease inhibitor 5) (Serine protease inhibitor 1-5) Serpina1e Dom5 Spi1-5 1,15E-07 1,41 3,37E-06 1,03 1,68E-04 0,10 6,52E-01 (Serine protease inhibitor A1e) (Serpin A1e)

CLUS_MOUSE Q06890 Clusterin (Apolipoprotein J) (Apo-J) (Clustrin) (Sulfated glycoprotein 2) (SGP-2) Clu Apoj Msgp-2 1,76E-04 -0,07 1,90E-01 0,29 1,41E-05 -0,09 8,67E-02 [Cleaved into: Clusterin beta chain; Clusterin alpha chain] CALB2_MOUSE Q08331 Calretinin (CR) Calb2 2,16E-02 0,25 2,63E-04 -0,12 4,71E-02 0,06 2,82E-01 PADI2_MOUSE Q08642 Protein-arginine deiminase type-2 (EC 3.5.3.15) (Peptidylarginine deiminase II) Padi2 Pad2 Pdi Pdi2 4,20E-02 0,17 7,74E-03 -0,16 9,63E-03 0,14 2,61E-02 (Protein-arginine deiminase type II) MYO1D_MOUSE Q5SYD0 Unconventional myosin-Id Myo1d 2,55E-02 0,08 2,27E-03 -0,08 1,21E-03 0,02 3,70E-01 CD166_MOUSE Q61490 CD166 antigen (Activated leukocyte cell adhesion molecule) (BEN) (Protein DM- Alcam 4,20E-02 -0,05 2,05E-01 -0,08 3,12E-02 0,01 7,47E-01 GRASP) (CD antigen CD166) GDIB_MOUSE Q61598 Rab GDP dissociation inhibitor beta (Rab GDI beta) (GDI-3) (Guanosine diphosphate Gdi2 Gdi3 4,89E-02 0,11 2,83E-03 -0,04 2,20E-01 -0,02 6,16E-01 dissociation inhibitor 2) (GDI-2)

HPT_MOUSE Q61646 Haptoglobin (Zonulin) [Cleaved into: Haptoglobin alpha chain; Haptoglobin beta Hp 2,74E-05 0,18 3,94E-01 1,14 1,64E-05 -0,20 3,43E-01 chain] PZP_MOUSE Q61838 Pregnancy zone protein (Alpha-2- macroglobulin) (Alpha-2-M) [Cleaved into: Pzp A2m 1,56E-03 0,23 2,12E-02 0,33 2,17E-03 0,13 1,70E-01 Alpha-2-macroglobulin 165 kDa subunit; Alpha-2-macroglobulin 35 kDa subunit] CSPG2_MOUSE Q62059 Versican core protein (Chondroitin sulfate proteoglycan core protein 2) (Chondroitin Vcan Cspg2 8,60E-04 0,03 1,04E-01 -0,10 7,93E-06 0,00 9,07E-01 sulfate proteoglycan 2) (Large fibroblast proteoglycan) (PG-M) DDX3X_MOUSE Q62167 ATP-dependent RNA helicase DDX3X (EC 3.6.4.13) (D1Pas1-related sequence 2) Ddx3x D1Pas1-rs2 Ddx3 (DEAD box RNA helicase DEAD3) 6,27E-04 -0,31 2,41E-05 0,04 4,62E-01 -0,01 8,22E-01 Dead3 Erh (mDEAD3) (DEAD box protein 3, X- chromosomal) (Embryonic RNA helicase) IF4G1_MOUSE Q6NZJ6 Eukaryotic translation initiation factor 4 gamma 1 (eIF-4-gamma 1) (eIF-4G 1) (eIF- Eif4g1 3,61E-03 -0,08 2,61E-03 0,10 3,97E-04 -0,05 2,79E-02 4G1) VAT1L_MOUSE Q80TB8 Synaptic vesicle membrane protein VAT-1 Vat1l Kiaa1576 3,58E-02 0,04 5,75E-01 0,16 2,62E-02 -0,08 2,37E-01 homolog-like (EC 1.-.-.-) FIBB_MOUSE Q8K0E8 Fibrinogen beta chain [Cleaved into: Fgb 1,56E-03 0,02 8,70E-01 0,47 2,14E-04 -0,05 6,46E-01 Fibrinopeptide B; Fibrinogen beta chain] SPA3N_MOUSE Q91WP6 Serine protease inhibitor A3N (Serpin A3N) Serpina3n Spi2 1,25E-02 -0,58 3,42E-03 0,72 6,03E-04 -0,28 1,33E-01

HEMO_MOUSE Q91X72 Hemopexin Hpx Hpxn 4,02E-06 0,10 3,32E-01 0,74 5,93E-07 0,05 6,40E-01 TRFE_MOUSE Q921I1 Serotransferrin (Transferrin) (Beta-1 metal- Tf Trf 2,09E-03 -0,21 1,10E-01 0,66 3,08E-05 0,00 9,96E-01 binding globulin) (Siderophilin) PSIP1_MOUSE Q99JF8 PC4 and SFRS1-interacting protein (Lens epithelium-derived growth factor) Psip1 Ledgf 1,91E-02 -0,08 2,25E-02 -0,05 1,10E-01 0,00 9,46E-01 (mLEDGF) PBDC1_MOUSE Q9D0B6 Protein PBDC1 (Polysaccharide biosynthesis domain-containing protein 1) Pbdc1 1,14E-02 -0,18 4,68E-04 0,00 9,15E-01 -0,05 2,43E-01

GATM_MOUSE Q9D964 Glycine amidinotransferase, mitochondrial (EC 2.1.4.1) (L-arginine:glycine Gatm 1,73E-02 -0,33 4,34E-04 0,14 8,13E-02 -0,27 2,02E-03 amidinotransferase) (Transamidinase) SNP29_MOUSE Q9ERB0 Synaptosomal-associated protein 29 (SNAP-29) (Golgi SNARE of 32 kDa) (Gs32) (Soluble 29 kDa NSF attachment protein) Snap29 1,73E-02 0,09 3,80E-01 0,38 1,81E-03 -0,03 7,84E-01 (Vesicle-membrane fusion protein SNAP- 29)

Figure S1. Disulfide HMGB1 induces cytokine and chemokine expression in the microglial cell line N13. Bar graphs represents mRNA levels for A) Tnf, B) Ccl2, C) Il1b and D) Il6 in

N13 cells 6 h following stimulation with disulfide HMGB1 (1 μg/ml) or no stimulation. Data are represented as mean ± SEM, n=3-4 experimental replicates/group, **p<0.01, ***p<0.001 vs. unstimulated group. Unstim: unstimulated, dsHMG: disulfide HMGB1.

Figure S2. Haptoglobin does not prevent or reverse disulfide-HMGB1 induced mechanical hypersensitivity in male and female mice. (A) Representative western blot images and (B) quantification of haptoglobin (HPT) immunopositive bands normalized to GAPDH and presented as percentage change to vehicle control groups. Withdrawal response prior to, 6 h and

24 h after the first day i.t. co-injection of disulfide HMGB1 (1 μg/mouse) with either haptoglobin

(10 μg/mouse) or vehicle (PBS), and 6 h after the second day i.t. injection of haptoglobin (10

μg/mouse) or vehicle in (C) male and (D) female mice. Data are presented as mean ± SEM, n=6 mice/group for western blot results and n=5 mice/group for behavioral results, *p<0.05,

**p<0.01 vs. control groups.