A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice

Abstract

There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but not CD11b+ cells. Consistent with this phenotype and the function of slc15a4, induction of IFN-I was virtually absent systemically and via cutaneous gene expression. Induction of other inflammatory cytokines (cytokine storm) was modestly blunted in slc15a4feeble except for inflammasome-associated genes consistent with slc15a4 being required for TLR7-mediated (but not inflammasome-mediated) inflammation downstream of IMQ. Surprisingly, only IFN-I gene expression was suppressed within IMQ-treated skin. Other genes including conserved psoriasiform trademark gene expression were augmented in slc15a4feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.

Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels

“…N-(Poly(ethylene glycol))-cis-5-norbornene-exo-2,3-dicarboximide 2 was directly accessed starting from commercially available exo-norbornene carboxylic anhydride. Upon condensation reaction with an amino-capped methoxy-poly-(ethylene glycol) in toluene, exo-imide 2 was obtained in nearly quantitative yield and confirmed by 1 H and 13 C NMR, as well as COSY, HSQC, and HMBC measurements (Figures S1−S5).…”

“…Consequently, in a simple purification step, the exo-acid could be extracted from the endo-derived iodolactone, as described in the Supporting Information, and subsequently esterificated with pentafluorophenol under Steglich conditions with DCC and DMAP. 41,42 The resulting exo-norbornene-5-carboxylic acid-pentafluorophenyl ester 3 was obtained in 90% yield and characterized by 1 H, 13 C, and 19 F NMR, as well as COSY, HSQC, and HMBC measurements (Figures S6−S11).…”

“…1 H NMR (300 MHz, CDCl 3 ): δ 6.23 (dd, J = 5.7, 2.9 Hz, 1H,), 6.18 (dd, J = 5.7, 3.0 Hz, 1H), 3.27 (ddq, J = 3.1, 1.5, 0.8 Hz, 1H), 3.03 (s, 1H), 2.59 (ddd, J = 9.0, 4.5, 1.5 Hz, 1H), 2.16−1.89 (m, 1H), 1.60−1.55 (m, 1H), 1.54 (t, J = 1.7 Hz, 1H), 1.52−1.47 (m, 1H) (Figures S6 and S8). 13 S11).…”

“…1 H NMR (300 MHz, CDCl 3 ) δ [ppm] = 6.26 (t, J = 1.9 Hz, 2H), 3.71−3.49 (m, 44H), 3.36 (s, 3H), 3.25 (p, J = 1.7 Hz, 2H), 2.66 (d, J = 1.3 Hz, 2H), 1.47 (dt, J = 9.8, 1.6 Hz, 1H), 1.34 (dt, J = 9.9, 1.6 Hz, 1H) (Figures S1 and S3). 13 Synthesis of exo-Norbornene-carboxylic Acid-Pentafluorophenyl Ester 3. The procedure was adapted from the literature 33 (Scheme S2).…”

“…10−12 This may even trigger life-threatening inflammatory cascade reactions, e.g., cytokine storms. 13 Alternatively, the conjugation of a small-molecule IMDQ to a nanoparticulate carrier was shown by others and us to improve the pharmacokinetic parameters and constrain the immune activity to the site of interest. 14−20 The covalent attachment of IMDQ to a poly-(methacrylamide)-based nanogel carrier was shown to result in a more defined pharmacological profile in terms of spatial control upon peritumoral injection and accumulation in the draining lymph nodes.…”