Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin

Abstract

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 (Itgβ1) 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 Itgβ1 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.

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

“…As reported previously, loss of integrin beta1 (itgβ1) from the epidermal compartment in mouse embryonic skin (cKO), leads to an augmentation of an inflammatory response characterized by increased macrophage cell infiltration and pro-remodeling fate acquisition (Kurbet et al, 2016 ; Bhattacharjee et al, 2021 ). However, the key metabolic pathways augmented by the epidermal compartment upon loss of itgβ1 remains to be uncovered.…”

“…We and others have shown that macrophages, an innate immune cell types, are the earliest responders to inflammatory cues in tissues (Kurbet et al, 2016 ; Bhattacharjee et al, 2021 ; Delavary et al, 2011 ). These macrophages exacerbate inflammation by acquiring an M2-like fate that cause exacerbated degradation the extra-cellular matrix by increased MMP synthesis.…”

Effects of Exercise or Mechanical Stimulation on Bone Development and Bone Repair

“…Stem Cells International Additionally, since it is not just about the individual cell behavior and cell crosstalk and interaction are involved, an in vivo study would expand our horizon for an integrative understanding of view of the bone repair and regeneration process. Recently, environmental cells, such as immune cells, endothelial cells, and pericytes, have been recognized to cooperate with tissue cells to facilitate tissue repair [63][64][65][66].…”

Epidermis Derived Lactate Promotes Sterile Inflammation by Inducing Metabolic Rewiring in Macrophages

“…We previously reported that under sterile inflammatory conditions, the skin resident macrophages acquire an enhanced proremodeling fate that leads to degradation of the extracellular matrix (3). This alternative fate acquisition by the macrophages leads to progression of the diseased condition through exacerbated ECM disruption (4). Interestingly, metabolic remodeling has been shown to complement fate decision in immune cells (5,6).…”

“…As reported previously, loss of integrin beta1 (itg1) from the epidermal compartment in mouse embryonic skin, leads to augmentation of an inflammatory response characterized by increased macrophage cell infiltration and pro-remodeling fate acquisition (3,4). To gain insights into the metabolic states of macrophages and its niche cells, we used a previously generated NGS data from the epidermis, macrophages and fibroblasts of WT and itg1cKO embryonic skin and identified differentially expressed metabolic pathways in cKO epidermis (4).…”