Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin

Area of Science:

• Immunology
• Dermatology
• Cell Biology

Background:

• Macrophages are key responders to tissue stress, but early inflammatory events remain unclear.
• Understanding cell communication in sterile inflammation is crucial for disease insight.

Purpose of the Study:

• To investigate the roles of embryonic skin epithelia and macrophages in initiating sterile inflammation.
• To identify cell-cell communication pathways driving early inflammatory responses in the skin.

Main Methods:

• Utilized next-generation sequencing (NGS) in an integrin beta 1 (Itgβ1) epidermis-specific knockout mouse model.
• Analyzed embryonic skin macrophages, keratinocytes, and fibroblasts.
• Employed macrophage depletion (CSF1R blockade) and pharmacological inhibition (celecoxib).

Main Results:

• Keratinocytes and macrophages, not fibroblasts, critically respond to sterile inflammatory cues.
• Epidermis releases damage-associated molecular patterns (DAMPs) and cytokines, activating macrophages.
• Macrophages adopt M2-like phenotypes, promoting extracellular matrix (ECM) remodeling and basement membrane disruption.
• Macrophage depletion or COX2 inhibition (via celecoxib) mitigates inflammation and ECM damage.

Conclusions:

• A crucial crosstalk exists between skin epithelia and dermal macrophages, initiating sterile inflammation.
• Epidermal cytokine production, mediated by COX2, dictates macrophage fate.
• These findings offer insights into early inflammatory events in skin and other disorders.