Mammalian cells autonomously activate hypoxia-inducible transcription factors to ensure survival in low-oxygen environments. We report that injury-induced hypoxia is insufficient to trigger hypoxia-inducible factor 1 alpha (HIF1α) in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that RORγt + γδ T cell–derived interleukin (IL)-17A, is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and ERK1/2 signaling proximal of IL-17RC activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A–HIF1α drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell–derived inputs in cellular adaptation to hypoxic stress during repair.

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

Ubiquilin 2 (UBQLN2) is an amyotrophic lateral sclerosis-linked molecular chaperone with a prion-like domain that directly engages ubiquitin to triage clients for proteasomal degradation. Dao et al. (2018) now establish that UBQLN2 forms ubiquitin-labile liquids, which may enable UBQLN2 to specifically extract ubiquitylated clients from stress granules for degradation.

Macrophages are essential components of the innate immune response to bacteria. While these cells must mount an inflammatory response to harmful pathogens, they require tight regulation to prevent host damage. One way in which macrophages attenuate inflammatory signaling cascades is through ubiquitination. This post-translational modification can target a protein substrate for downstream signaling or for degradation. E3 ubiquitin ligases are required to facilitate the formation of these chains. Nedd4-family interacting protein 1 (Ndfip1) activates multiple E3 ubiquitin ligases, including Itch, which is crucial for attenuating cytokine production by T cells, and Nedd 4-2, which is required for iron regulation by neurons. While Itch has been shown to limit macrophage activity, it is unclear how Ndfip1 functions in macrophages, and how it affects macrophage antibacterial responses. We generated mice lacking Ndfip1 in myeloid cells (Ndfip1fl/fl LysM Cre). Unlike mice lacking Ndfip1 in T cells, these mice have no evidence of inflammation at baseline. Upon i.n. infection with Klebsiella pneumoniae, Ndfip1 fl/fl LysM Cre mice show reduced bacterial loads three days post infection, despite normal innate cell recruitment. This result could be recapitulated when mice were infected intraperitoneally. Peritoneal macrophages lacking Ndfip1 have unchanged cytokine responses when stimulated with K. pneumonia, suggesting Ndfip1 attenuates macrophage activity through a mechanism other than limiting cytokine production. This project may reveal new mechanisms used by myeloid cells in eliminating bacteria, providing insight into the regulatory mechanisms that prevent excess inflammation.

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