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Preprint WatchModerateOctober 13th, 2026

Anti-inflammatory macrophages limit endothelial inflammation and restrict neutrophil recruitment through Gas6/AXL signaling

Ignes-Romeu, A.; Sood, R.; Hind, L. E.

Gas6 secreted by anti-inflammatory macrophages signals through AXL to limit endothelial activation, reduce ICAM-1 upregulation, maintain VE-cadherin and restrict neutrophil extravasation in a primary human three-dimensional inflammation-on-a-chip model, and AXL inhibition increases extravasation.

Moderate contradiction

2 prior failures

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

Two AXL programmes sit in the Claidex graph and neither produced a clean read on the target. Bemcentinib plus pacritinib in advanced lung adenocarcinoma stopped at four patients on investigational drug supply limits, before any efficacy or pharmacodynamic readout (bemcentinib-axl-lung-adenocarcinoma-phase1b2-supply-termination), and SAPPHIRE randomised 577 patients with post-checkpoint non-squamous non-small cell lung cancer to sitravatinib plus nivolumab and missed overall survival, hazard ratio 0.86, 95 percent CI 0.70 to 1.05 (sitravatinib-axl-tam-post-checkpoint-nsclc-sapphire-phase3-translational-mismatch). This preprint reports that Gas6 acting through AXL on anti-inflammatory macrophages restrains endothelial activation and limits neutrophil extravasation in a primary human model, and that inhibiting AXL increases extravasation. That is a protective role for AXL signalling at the vascular interface, which runs opposite to the therapeutic logic of both clinical programmes, each of which inhibited AXL to relieve immune suppression. The flag is raised on target overlap and directional tension rather than on a replicated contradiction, because the preprint uses an in vitro human model with no disease endpoint. It does suggest that on-target vascular inflammation is a plausible cost of systemic AXL inhibition and worth measuring directly in any future AXL programme.

Abstract excerpt

Neutrophil extravasation requires coordinated interactions between the endothelium and surrounding cells, including tissue resident macrophages. Macrophages adopt distinct polarization states in the tissue environment, positioning them as regulators of vascular inflammation. However, how these states influence barrier function and neutrophil extravasation remains unclear. Here, we polarized macrophages in the matrix surrounding an endothelial vessel, in a three-dimensional inflammation-on-a-chip model developed only from primary human cells. We found anti-inflammatory macrophages limited endothelial inflammation, reducing ICAM-1 upregulation, maintaining VE-Cadherin expression, halving permeability relative to pro-inflammatory devices, and reducing neutrophil extravasation and migration relative to macrophage-free devices. Secretome profiling identified Gas6, an AXL ligand, as a potential regulator of these effects. Inhibiting AXL increased extravasation in devices with anti-inflammatory macrophages, and soluble Gas6 reduced extravasation in macrophage-free devices, implicating Gas6 as a mediator of this regulation. This indicates macrophages regulate endothelial inflammation and the neutrophil response via Gas6 signaling.

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.