Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.

Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.

Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin.

Macrophages are highly responsive to the environmental cues and are the primary responders to tissue stress and damage. While much is known about the role of macrophages during inflammatory disease progression; the initial series of events that set up the inflammation remains less understood. In this study, we use next generation sequencing (NGS) of embryonic skin macrophages and the niche cells - skin epithelia and stroma in the epidermis specific knockout of integrin beta 1 (Itgß1) model to uncover specific roles of each cell type and identify how these cell types communicate to initiate the sterile inflammatory response. We demonstrate that while the embryonic skin fibroblasts in the Itgß1 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 remodeling 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 a critical crosstalk between the epithelia and the dermal macrophages that shapes macrophage fate and initiates sterile inflammation in the skin. The insights gained from our study can be extrapolated to other inflammatory disorders to understand the early events that set up the disease.

Unraveling the ECM-Immune Cell Crosstalk in Skin Diseases.

The extracellular matrix (ECM) is a complex network of proteins and proteoglycans secreted by keratinocytes, fibroblasts and immune cells. The function of the skin ECM has expanded from being a scaffold that provides structural integrity, to a more dynamic entity that is constantly remodeled to maintain tissue homeostasis. The ECM functions as ligands for cell surface receptors such as integrins, dystroglycans, and toll-like receptors (TLRs) and regulate cellular signaling and immune cell dynamics. The ECM also acts as a sink for growth factors and cytokines, providing critical cues during epithelial morphogenesis. Dysregulation in the organization and deposition of ECMs lead to a plethora of pathophysiological conditions that are exacerbated by aberrant ECM-immune cell interactions. In this review, we focus on the interplay between ECM and immune cells in the context of skin diseases and also discuss state of the art therapies that target the key molecular players involved.