Dendritic cells (DCs) are highly mechanosensitive cells. We have shown that deformation of their nucleus during cell migration leads to DC transcriptional reprogramming and CCR7 upregulation at their surface. This relies on the lipid metabolism enzyme cPLA₂, which translocates into the DC nucleus upon stretching of the nuclear envelope to produce arachidonic acid and derivatives. These results prompted us investigating the reciprocal relationship between this program of DC mechanical maturation and tissue fibrosis, which results from excessive deposition and cross-linking of collagen, profoundly altering tissue mechanical properties.

Using the bleomycin-induced skin fibrosis model, we observed that dermal thickening coincided with extensive remodelling of the white adipose tissue, where adipocytes were replaced by an aligned collagen network. DC migration from the skin to draining lymph-nodes was progressively lost during fibrosis establishment and CCR7⁺ DCs accumulated within the fibrotic skin. Interestingly, two main skin DC niches were observed: (1) around Lyve1⁺CD31⁺ CCL21⁺ lymph vessels next to dermal hair follicles, and (2) around Lyve1⁻CD31⁺CCL19⁺ blood vessels within the remodelled white adipose tissue. Our preliminary results indicate that cPLA₂-deficient DCs show decreased accumulation in this second niche, which is marked by high expression of lysyl-oxidase enzymes that cross-link and align collagen fibers. These data are consistent with blood vessels of fibrotic skin being an active site for DC mechanical maturation and retention. In addition, we unexpectedly observed that cPLA₂ deletion in CD11c⁺ cells limited the establishment of fibrosis itself, suggesting the contribution of this pathway to extracellular matrix remodelling. These findings highlight that DC migration and tissue distribution is altered in tissue fibrosis and reveal a potential mechanistic link between myeloid cell mechanosensing and fibrotic progression.