Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1–dependent.

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Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1–dependent pathways Victoria J. Philbin, DPhil, David J. Dowling, PhD, Leighanne C. Gallington, BSc, Guadalupe Cortés, PhD, Zhen Tan, MD, Eugénie E. Suter, MA, Kevin W. Chi, BA, Ariel Shuckett, MPH, Liat Stoler-Barak, MSc, Mark Tomai, PhD, Richard L. Miller, PhD, Keith Mansfield, DVM, Ofer Levy, MD, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 1, Pages 195-204.e9 (July 2012) DOI: 10.1016/j.jaci.2012.02.042 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TLR7/8 and TLR8 agonists are more potent and effective than alum in inducing TNF and IL-1β from human newborn and adult monocytes. Newborn (A and B) or adult (C and D) monocytes were stimulated for 4 (TNF) or 18 (IL-1β) hours, and supernatants were assayed by means of ELISA (n = 3-4). *P ≤ .05, Mann-Whitney test comparing TLR agonist with alum. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The TLR8 agonist 3M-002 induces greater TLR pathway mRNA upregulation and TH1-polarizing cytokine/chemokine levels from neonatal monocytes than a TLR7 agonist. Monocytes (5 × 107 cells/mL) were stimulated with the indicated agonist (50 μmol/L) for 4 hours. A, Agonist-induced mRNA fold change relative to control (colored lines indicate 2-fold change). B-D, TH1, TH2 (± TH1), TH17, and anti-inflammatory proteins (n = 3-6). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TLR8 agonists are refractory to inhibitory adenosine/cAMP and associated with less cAMP accumulation in newborn monocytes. A, Monocytes to which adenosine (10 μmol/L) or saline (Sal) added before stimulation with agonists (50 μmol/L) for 2 hours (representative of 3-6 experiments). B, Percentage cytokines. C, cAMP concentrations in agonist-treated monocytes. D, Thirty-minute db-cAMP (10 μmol/L)–treated monocytes, 4 hours of stimulation (n = 3-6). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Newborn MoDCs display diminished LPS/ATP-induced but robust IMQ-induced caspase-1 activation and IL-1β production. A-F, Newborn and adult MoDCs stimulated with LPS (2 hours; Fig 4, A-C) or 3M-002 (24 hours; Fig 4, D-F) plus 5 mmol/L ATP as indicated are shown. Supernatant assayed IL-1β (ELISA; Fig 4, A and D), cell lysate caspase-1 by means of Western blotting/densitometry (Fig 4, B, C, E, and F). Fig 4, C and F, Representative of n = 3; Fig 4, A and D, n = 4-6. Asterisks denote comparison between treatment conditions. Bars indicate comparison between groups (newborn and adult). G, Caspase-1 inhibitor Z-WEHD-FMK pretreatment of neonatal MoDCs treated as above. H, IL-1β data from Fig 4, G, shown as a percentage (n = 4-6). *P < .05, **P < .01, and ***P < .001. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; N.S., not significant. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Proposed mechanisms of IMQ TLR8 agonist activation of human newborn monocytes and DCs through adenosine-refractory and caspase-1-dependent pathways. 3M-002 agonists are refractory to the inhibitory effects of the adenosine/cAMP pathway, which skews neonatal immunity against TH1 polarization (A) and can overcome impaired IL-1β responses of neonatal DCs to LPS/ATP (B) independently of exogenous ATP (C). Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Neonatal monocytes mount a greater TLR pathway transcriptional response and TH1-polarizing cytokine/chemokine production to TLR8 agonist than to TLR2/6 agonist. Monocytes (5 × 107 cells/mL) were stimulated with control buffer, 1 μg/mL MALP, or 50 μmol/L 3M-002 for 4 hours. A, Agonist-induced mRNA fold change relative to control (colored lines indicate 2-fold change). B-D, TH1, TH2 (± TH1), TH17, and anti-inflammatory proteins (n = 3-6). *P < .05. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 siRNA targeting TLR8 selectively inhibits 3M-002–induced TNF production in human newborn MoDCs. A, Dose-dependent action of siRNA TLR8 on TLR8 mRNA expression relative to the nontargeting “siRNA neg.” B, Specific effect of siRNA TLR8 on TLR8 mRNA expression relative to TLR7 mRNA. C, Percentage inhibition in TLR8-induced (5 or 50 μmol/L) TNF production after siRNA TLR8 transfection (n = 4-6). *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 3M-002 induces greater TH1 cytokine and costimulatory molecule expression in newborn MoDCs than 3M-013 or alum. A and B, Differentiation of monocytes to MoDCs (Fig E3, A) and agonist-induced costimulatory markers (Fig E3, B) observed in neonatal MoDCs stimulated with buffer, alum (0.5, 5, or 50 μg/mL), 3M-002, or 3M-013 (5 or 50 μmol/L) for 24 hours. FI, Fluorescence intensity. C-F, Supernatant cytokines (n = 3-8). *P < .05, **P < .01, and ***P < .001 comparing 50 μg/mL alum with TLR agonists (gray bars) or TLR7 to TLR8 (black bars). Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 TLR7 and TLR7/8 agonists induce IFN-α production and upregulation of pDC CD40 in human neonatal and adult blood, upregulation of costimulatory expression in MoDCs, and upregulation of CD40 expression in infant rhesus macaque mDCs. A and B, Human newborn cord and adult peripheral blood incubated for 19 hours with agonists at the indicated concentrations or at 5 μmol/L and supernatants analyzed for IFN-α (by means of ELISA; Fig E4, A) and pDC CD40 expression (Fig E4, B; n = 3-9). Gray/black arrows with color-matched stars depict comparisons. C, Neonatal MoDC expression of TLR7/8-induced costimulatory markers at 24 hours (n = 3-8). D, mDC CD40 expression in infant rhesus macaque (1-4 months) peripheral blood stimulated ex vivo for 19 hours with control or 5 μmol/L R848. Median fluorescence intensity (FI) minus isotype depicted (n = 4). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Alum- and TLR agonist–induced expression of inflammasome genes in human newborn MoDCs. Neonatal MoDCs (1 × 106 cells/mL) stimulated with buffer, alum (50 μg/mL), 3M-013 (50 μmol/L), or 3M-002 (50 μmol/L) for 4 hours. Expression of mRNAs in the inflammasome pathway measured and analyzed according to the manufacturer's instructions (ΔΔCt method normalized to housekeeping genes). Fold change was calculated relative to buffer control (n = 4). *P < .05. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 3M-002 activates caspase-1–dependent IL-1β production in neonatal MoDCs independently of ATP. A, Neonatal MoDCs were stimulated with buffer, alum, LPS, or 3M-002 for 2 or 24 hours plus 5 mmol/L ATP, as indicated. IL-1β in the supernatants was assayed by means of ELISA. B, IL-1β data expressed as a percentage relative to agonist. **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 TLR8 agonists induce robust production of TNF and IL-1β in whole blood of neonatal and infant rhesus macaques. Whole blood derived from mothers after delivery (DAM, n = 5-8), nonpregnant adult control subjects (NON-DAM, n = 4-5), newborns (CORD, n = 4), and infants (peripheral blood; n = 6-13) was incubated with 1 μg/mL Mycoplasma species–associated lipopeptide (TLR2/6), 3M-013, R848, or 3M-002 (all 50 μmol/L) for 4 hours. Supernatant TNF (A-D) or IL-1β (E-H) levels were measured by means of ELISA. Color-matched arrows and stars depict comparisons. *P ≤ .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 195-204.e9DOI: (10.1016/j.jaci.2012.02.042) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions