Skin-resident innate lymphoid cells converge on a pathogenic effector state

Area of Science:

• Immunology
• Cell Biology
• Dermatology

Background:

• Tissue-resident innate lymphoid cells (ILCs) are key players in barrier immunity and local responses.
• ILCs are classified into subtypes (ILC1, ILC2, ILC3) based on transcription factors and cytokine profiles.
• In psoriasis, ILC3-associated cytokines IL-17 and IL-22, driven by IL-23, contribute to skin inflammation.

Purpose of the Study:

• To investigate whether psoriatic inflammation is initiated by pre-committed ILCs or through cell-state transitions.
• To characterize the dynamic transcriptional landscape of skin ILCs during the induction of psoriasis.

Main Methods:

• Induction of psoriasis in mice using IL-23 or imiquimod.
• Single-cell RNA sequencing (scRNA-seq) of skin ILCs over a time course.
• In vitro experiments, single-cell ATAC sequencing (scATAC-seq), and in vivo fate mapping.

Main Results:

• Psoriatic inflammation reconfigures a spectrum of skin ILCs, converging on a pathogenic ILC3-like state.
• Tissue-resident ILCs, not circulatory ILCs, were sufficient to drive pathology.
• scRNA-seq revealed a transcriptional continuum of fluid ILC states, shifting towards an ILC3-like phenotype upon disease induction.
• Quiescent-like and ILC2 ILC states were confirmed to have transition potential.

Conclusions:

• Skin ILCs exhibit remarkable plasticity, transitioning between states in response to inflammatory triggers.
• The dynamic adaptation of immune cells in healthy tissues can lead to pathological remodeling if unchecked.
• Understanding these cell-state transitions is crucial for developing targeted therapies for inflammatory skin diseases like psoriasis.