Sestrin and the Consequences of Aging: The protein kinase TOR (target of rapamycin) plays key roles in the control of fundamental biological processes, including growth, metabolism, aging, and immune function. Sestrin proteins show increased abundance in response to stress and have been implicated in control of TOR activity. Lee et al. (p. 1223 ; see the Perspective by Topisirovic and Sonenberg ) characterized Drosophila fruit flies lacking sestrins. Sestrins were implicated in a negative feedback loop in which the abundance of sestrins is controlled by TOR activity with sestrins concomitantly also inhibiting activity of TOR. Furthermore, flies lacking sestrins showed accumulation of fat, muscle degeneration, and heart abnormalities similar to those that plague aging humans with a sedentary life-style.

The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2⁺ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2⁺ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2⁺ myeloid cells, CCR7⁺LAMP3⁺ dendritic cells, and CXCR4 expressed on both CD8⁺ Tc17 cells and keratinocytes, respectively. The SFRP2⁺ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.