Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin.

Oindrila Bhattacharjee,Florent Ginhoux,Uttkarsh Ayyangar,Ambika S Kurbet,Vairavan Lakshmanan,Srikala Raghavan,Dasaradhi Palakodeti

doi:10.3389/fimmu.2021.718005

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.

Highlights

The skin, our largest organ, protects underlying tissues from physical, chemical and pathogenic stresses and comprises of the ectoderm-derived epidermis and mesoderm-derived dermis separated by a meshwork of extracellular matrix (ECM) proteins known as the basement membrane (BM)
We show that the sterile inflammation in the integrin beta 1 (Itgb1) KO skin is primarily driven by the epithelial and macrophage compartment
The skin epithelia responds to the loss of Itgb1 by upregulating the expression of cytokines, chemokines and

Summary

Introduction

The skin, our largest organ, protects underlying tissues from physical, chemical and pathogenic stresses and comprises of the ectoderm-derived epidermis and mesoderm-derived dermis separated by a meshwork of extracellular matrix (ECM) proteins known as the basement membrane (BM). Several studies have suggested that sterile inflammation is initiated primarily by the innate immune cells such as macrophages [5,6,7]. Suggest that the macrophages acquire a mixed signature which is, in part, a result of a large repertoire of cues received from multiple cell types in the tissue [11]. These studies highlight a major gap in the understanding of how tissue macrophages integrate signals from their niches to acquire distinct functional states and how that may, in turn, influence tissue homeostasis. Studies from our lab, and others, have shown that embryonic macrophages hold potential to actively participate in inflammatory conditions [14, 15]

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Conclusion