Preprint Watch 2026-07-29: 2 Clinical Failures Flagged for TLR9 | Claidex

Claidex Preprint Watch

doi:10.1101/2025.11.20.689413

Preprint WatchModerateJuly 29th, 2026

Gelsolin Counteracts ER Stress-Driven Inflammatory Circuits in Psoriasis-like Dermatitis

Ori, D.; Okude, H.; Konishi, R.; Murase, M.; Hiroki, S.; Takahara, S.; Tanaka, T.; Toyodome, R.; Kano, N.; Kawasaki, T.; Ishii, K.; Kobiyama, K.; Nakashima, H.; Nakashima, K.; Sasai, M.; Yamamoto, M.; Kumagai, Y.; Tsuru, A.; Kohno, K.; Kawai, T.

Extracellular mitochondrial DNA and the antimicrobial peptide mBD14, both released downstream of imiquimod-induced ER stress, cooperatively stimulate plasmacytoid dendritic cells through TLR9 to establish a feed-forward inflammatory loop, with gelsolin acting as an intrinsic brake on the upstream ER stress.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint places TLR9 at the centre of a feed-forward inflammatory loop in psoriasis-like dermatitis, driven by mitochondrial DNA and an antimicrobial peptide acting on plasmacytoid dendritic cells. Claidex holds two TLR9 post-mortems, both from the opposite therapeutic direction. In vidutolimod-tlr9-cmp001-merkel-cell-carcinoma-phase2-supply-termination and vidutolimod-tlr9-cmp001-metastatic-melanoma-phase2-3-business-termination, a TLR9 agonist was advanced to amplify the same plasmacytoid dendritic cell axis for antitumour benefit, and both programmes ended without a definitive efficacy answer. The preprint does not contradict either post-mortem, and the disease context differs, but it sharpens a question the oncology programmes never resolved: whether TLR9 engagement in humans produces a self-limiting stimulus or a self-amplifying one whose magnitude is set by tissue context rather than by dose. Programmes on either side of TLR9, agonist or antagonist, should carry a pharmacodynamic readout capable of distinguishing those two regimes.

Abstract excerpt

Psoriasis is a chronic inflammatory skin disorder driven by amplified communication between immune cells and keratinocytes. Here, we show that imiquimod (IMQ) triggers organelle stress responses that directly contribute to this pathogenic circuit. In dendritic cells (DCs), IMQ promotes formation of ER-mitochondria contact sites (MAMs), inducing ER stress and activation of the unfolded protein response (UPR). These pathways act independently of, yet converge with, TLR7/MyD88 signaling to enhance IL-23 expression. IMQ also increases cytosolic Ca{superscript 2}+, facilitating NLRP3 inflammasome activation and release of mitochondrial DNA (mtDNA). In parallel, keratinocytes exposed to IMQ activate UPR-dependent genes, including Defb14 (mBD14), a psoriasis-associated antimicrobial peptide. Extracellular mtDNA and mBD14 then cooperatively stimulate plasmacytoid DCs through TLR9, establishing a feed-forward inflammatory loop. We further identify Gelsolin as a direct IMQ-binding protein that mitigates IMQ-induced ER stress; its loss amplifies ER stress, UPR activation, and oxidative stress, and its expression is reduced in human psoriatic lesions. Thus, MAM-UPR signaling links intracellular organelle stress to the intercellular networks that drive psoriatic inflammation, with Gelsolin acting as a critical intrinsic safeguard.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.