Dermal White Adipose Tissue-Derived Il-33 Regulates Il-4/13 Expression in Myeloid Cells during Inflammation

Effective tissue response to infection and injury essentially relies on the fine-tuned induction and subsequent resolution of inflammation. Recent research highlighted multiple functions of dermal white adipose tissue (dWAT) beyond its traditional role as an energy reservoir. However, in contrast to other fat depots, there are only limited data about putative immune-regulatory functions of dWAT. Therefore, we investigated the impact of dWAT in the control of an acute skin inflammation. Skin inflammation triggers the activation of dWAT. In turn, soluble mediators of activated dWAT stimulate the expression of numerous genes controlling skin inflammation, including the T helper 2 cell cytokines Il4 and Il13, in myeloid cells in vitro. Consistently, myeloid cells isolated from inflamed skin showed a significant upregulation of Il-4/13 expression compared with those isolated from healthy skin. Mechanistically, we demonstrate that IL-33 released from activated dWAT is responsible for IL-4/13 stimulation in myeloid cells. Interestingly, obesity attenuates IL-33 secretion in dWAT during inflammation, resulting in decreased Il-4 and Il-13 expressions in myeloid cells. Our data reveal an IL-33-IL-4/13 signaling cascade initiated from dWAT in a T helper 2-independent context of inflammation that may contribute to limitation of inflammation. This cascade seems to be disturbed in individuals with obesity with prolonged inflammation.