Histone H1 boosts chemokine signaling and immune cell migration in a charge-dependent manner

Histones are released by neutrophils at sites of inflammation where they help immobilize and kill invading pathogens. However, the broader role of histones in pathogen protection remains elusive. In vitro cell signaling and 3D chemotaxis assays using human cell lines and primary human immune cells. Fluorescence polarization, NMR and chemical shift perturbation studies of protein-protein interactions. Here, we show that beyond antimicrobial activity, the globular domain of linker histone H1.0 (H1-GD) boosts immune activation. Specifically, H1-GD potentiates the activity of the chemokines CCL19 and CCL21 through their receptor CCR7, leading to increased signaling and immune cell chemotaxis. H1-GD also boosts the activity of CCL5 and CCL20 via CCR1/CCR5 and CCR6, respectively. H1-GD has a net charge of + 9 and interacts with the acidic N-terminal region of CCR7, providing an electrostatic basis for chemokine boosting activity. Using different charge variants of H1-GD, we show that its boosting activity can be modulated by altering both net charge and the position of charge. Linear peptides with similar net charge derived from the C-terminal tail of H1 lacked chemokine boosting activity, indicating that beyond net charge, an optimal spatial arrangement is required. Our findings suggest that H1-GD may act as enhancer of chemokine signaling, which in turn may lead to increased directed migration of immune cells towards sites where histone concentrations are elevated.