Microenvironmental and cell intrinsic factors governing human cDC2 differentiation and monocyte reprogramming

Area of Science:

• Immunology
• Dermatology
• Cell Biology

Background:

• Circulating blood cDC2s are abundant in peripheral tissues.
• Factors controlling cDC2 differentiation in tissues, especially during inflammation, are not well understood.

Purpose of the Study:

• To investigate the factors governing cDC2 differentiation in psoriatic skin.
• To understand how inflammatory signals influence cDC2 plasticity.

Main Methods:

• Analysis of psoriatic cDC2s for efferocytosis receptor Axl and signaling pathways.
• In vitro induction of Axl+ cDC2s from blood cDC2s using BMP7 and TGF-β1.
• Modeling cDC2 generation and differentiation using BMP7 and CD34+ hematopoietic progenitor cells.
• Investigation of p38MAPK role in cDC2 subset generation.
• Analysis of RelB+ cDC2s and KLF4 expression in cDC2s.

Main Results:

• Psoriatic cDC2s express Axl and show BMP and p38MAPK signaling.
• BMP7 and TGF-β1 induce Axl+ cDC2s from blood cDC2s in vitro.
• p38MAPK drives Axl+ cDC2s over Langerhans cells and promotes RelB+ cDC2s.
• BMP7 enables modeling of cDC2 and Langerhans cell differentiation from progenitor cells.
• cDC2s can acquire monocyte-derived DC and macrophage characteristics, including KLF4 expression.

Conclusions:

• Inflammatory signals in psoriatic skin instruct blood cDC2s to differentiate into various tissue-resident cell subsets.
• BMP7 and p38MAPK signaling are key regulators of cDC2 differentiation and plasticity.
• cDC2s exhibit remarkable plasticity, acquiring phenotypes of other myeloid lineages under inflammatory conditions.