PRJNA739149
Epithelial-Macrophage Crosstalk Drives Sterile Inflammation in Embryonic Skin
The conditional ablation of integrin-Beta1 in the epidermis leads to upregulation of the epidermal wound signatures. This is associated with an increased recruitment and activation of macrophages, increased inflammation, and disruption of the basement membrane in the Itg-Beta1 knockout skin. While previous work from our laboratory uncovered the response of the whole skin tissue, the specific roles played by distinct skin compartments in orchestrating the sterile inflammatory response are not well understood. In this study, we use next generation sequencing (NGS) of embryonic skin macrophages and the niche cells - skin epithelia and stroma, to uncover specific roles of each cell type and identify how these cell types communicate to drive the sterile inflammatory response. We demonstrate that while the embryonic skin fibroblasts in the Itg-Beta1 knockout skin are relatively inactive, the keratinocytes and macrophages are the critical responders to the sterile inflammatory cues. The epidermis expresses damage associated molecular patterns (DAMPs), stress response genes, pro-inflammatory cytokines, and chemokines that aid in eliciting the inflammatory response. The macrophages, in-turn, respond by acquiring enhanced M2-like characteristics expressing ECM remodelling and matrisome signatures that exacerbate the basement membrane disruption. Depletion of macrophages by blocking the CSF1 receptor (CSF1R) results in improved basement membrane integrity and reduced ECM remodeling activity in the KO skin. Further, blocking the skin inflammation with celecoxib reveals that the acquired fate of macrophages in the KO skin is dependent on its interaction with the epidermal compartment through COX2 dependent cytokine production. Taken together, our study highlights that a critical crosstalk between the epithelia and the dermal macrophages shapes macrophage fate and drives sterile inflammation in the developing embryonic skin.