Mammalian cells autonomously activate hypoxia-inducible transcription factors (HIFs) to ensure survival in low-oxygen environments. We report here that injury-induced hypoxia is insufficient to ...trigger HIF1α in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor γt
(RORγt
) γδ T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proximal of IL-17 receptor C (IL-17RC) activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A-HIF1α axis 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.
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.
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. now establish that UBQLN2 forms ubiquitin-labile liquids, which may enable UBQLN2 to specifically extract ubiquitylated clients from stress granules for degradation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aberrant epidermal differentiation is a hallmark of inflammatory skin diseases, including psoriasis and atopic dermatitis. If and how differentiated epidermal cells contribute to inflammatory ...pathology is unclear. In their new article in the Journal of Investigative Dermatology, Shao et al. (2021) report that IRAK2 signaling downstream of IL-1 and IL-36 links epidermal differentiation and skin inflammation.
The purpose of this study was to assess the feasibility and clinical impact of telemedicine-based opioid treatment with buprenorphine-naloxone following the Coronavirus disease 2019 pandemic.
...Participants included in this retrospective analysis consisted of adult New York City residents with opioid use disorder eligible for enrollment in the NYC Health+Hospitals Virtual Buprenorphine Clinic between March and May 2020 (n = 78). Follow-up data were comprised of rates of retention in treatment at 2 months, referrals to community treatment, and induction-related events.
During the initial 9 weeks of clinic operations, the clinic inducted 78 patients on to buprenorphine-naloxone and completed 252 visits. Patient referrals included non-NYC Health + Hospitals (n = 22, 28.2%) and NYC Health + Hospitals healthcare providers (n = 17, 21.8%), homeless shelter staff (n = 13, 16.7%), and the NYC Health + Hospitals jail reentry program in Rikers Island (n = 11, 14.1%). At 8 weeks, 42 patients remained in care (53.8%), 21 were referred to a community treatment program (26.9%), and 15 were lost to follow-up (19.2%). No patients were terminated from care due to disruptive behavior or suspicions of diversion or misuse of Buprenorphine. Adverse clinical outcomes were uncommon and included persistent withdrawal symptoms (n = 8, 4.3%) and one nonfatal opioid overdose (0.5%).
Telemedicine-based opioid treatment and unobserved home induction on buprenorphine-naloxone offers a safe and feasible approach to expand the reach of opioid use disorder treatment, primary care, and behavioral health for a highly vulnerable urban population during an unprecedented natural disaster.
In April 2020, in light of COVID-19-related blood shortages, the US Food and Drug Administration (FDA) reduced the deferral period for men who have sex with men (MSM) from its previous duration of 1 ...year to 3 months.Although originally born out of necessity, the decades-old restrictions on MSM donors have been mitigated by significant advancements in HIV screening, treatment, and public education. The severity of the ongoing COVID-19 pandemic-and the urgent need for safe blood products to respond to such crises-demands an immediate reconsideration of the 3-month deferral policy for MSM.We review historical HIV testing and transmission evidence, discuss the ethical ramifications of the current deferral period, and examine the issue of noncompliance with donor deferral rules. We also propose an eligibility screening format that involves an individual risk-based screening protocol and, unlike current FDA guidelines, does not effectively exclude donors on the basis of gender identity or sexual orientation. Our policy proposal would allow historically marginalized community members to participate with dignity in the blood donation process without compromising blood donation and transfusion safety outcomes.
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CEKLJ, DOBA, FSPLJ, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened ...metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
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•HIF1α is activated in psoriatic epidermis and associated with IL-17A•Ablating epithelial HIF1α curbs vascular, nervous, and immune skin pathology•HIF1α-induced epithelial glycolysis directs multisystemic skin pathology•Lactate, a glycolysis byproduct, potentiates the underlying γδ T17 response
How immune and epithelial cells simultaneously fuel their dysfunction in chronic skin diseases is unclear. Subudhi and Konieczny et al. find that IL-17-induced epithelial HIF1α activates glycolysis, which potentiates the γδ T17 response via lactate. This metabolic circuit drives multisystems pathology and can be targeted in inflammatory disease.
Abstract
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.
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.
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