Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus

Mistry, Pragnesh; Nakabo, Shuichiro; O’Neil, Liam J.; Goel, Rishi R.; Jiang, Kan; Carmona‐Rivera, Carmelo; Gupta, Sarthak; Chan, Diana; Carlucci, Philip M.; Wang, Xinghao; Naz, Faiza; Manna, Zerai; Dey, Amit; Mehta, Nehal N.; Hasni, Sarfaraz; Dell’Orso, Stefania; Gutierrez-Cruz, Gustavo; Sun, Hongwei; Kaplan, Mariana J.

doi:10.1073/pnas.1908576116

Cited by 192 publications

(200 citation statements)

References 45 publications

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“…Analysis of recently published human BM neutrophil gene expression data ( 37 ) also showed higher levels of expression for a number of antioxidant enzymes, such as GPX1,3,4 ; SOD2 ; HMOX2 ; TXNRD1 ; and SRXN1 in segmented mature neutrophils ( Supplemental Figure 6A ). A close look into the transcriptome of enriched CD10 + and CD10 – LDNs from SLE patients published by Mistry et al, revealed a highly similar pattern of increased expression of SOD2 , HMOX2 , SRXN1 , and TXNRD1 in mature CD10 + LDNs ( 38 ) ( Supplemental Figure 6, B and C ).…”

Section: Resultsmentioning

confidence: 70%

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Wang

Khoyratty

et al. 2020

JCI Insight

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Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b + CD15 + CD10 lo/– CD64 – band neutrophils and CD66b hi CD15 + CD10 lo/– CD64 +/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

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Section: Resultsmentioning

confidence: 70%

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Wang

Khoyratty

et al. 2020

JCI Insight

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“…Moreover, the underlying differences in lupus skin, such as enhanced IFN-I signaling 7,112,113 and defects in protective Langerhans cell population 114 could inform the extent and nature of neutrophil-mediated systemic responses. The exact mechanism might in addition be influenced by the neutrophil/LDG phenotype, as heterogeneity within these populations has become more apparent in SLE 65 . Our findings of elevated CXCR4 and ICAM1 hi CXCR1 lo (rTM) circulating populations, particularly in SLE LDGs, further add to this heterogeneity and suggest that some of the more pro-inflammatory granulocytes in blood might have prior "tissueexperience", i.e.…”

Section: Discussionmentioning

confidence: 99%

“…While both the aged (CXCR4 hi ) and the reverse migrating (ICAM1 hi CXCR1 lo ) neutrophil phenotypes have been associated with inflammatory functions and tissue injury in different murine models 51,52,60 , few studies have been performed on these cell populations in human disease. Given the emerging role of neutrophils in SLE 11,[15][16][17] and their apparent heterogeneity 18 , we investigated whether PMNs or low density granulocytes (LDGs) 64,65 from SLE patients demonstrated the phenotypes of aged, CXCR4 hi , or reverse migrating, ICAM1 hi CXCR1 lo , neutrophils. Flow cytometry profiling of PMNs and LDGs revealed higher CXCR4 expression on the surface of these cells in SLE patients, compared to healthy controls ( Fig.…”

Section: Figure 4: Uvb Light-triggered Neutrophil Migration To the Kimentioning

confidence: 99%

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Skopelja-Gardner

Tai

Sun

et al. 2020

Preprint

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Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients and can exacerbate local skin disease as well as systemic disease, including lupus nephritis. While neutrophils have been implicated in local tissue injury in lupus in response to immune complex deposition, whether and how they play a role in photosensitivity induced systemic disease is unknown. Here, we show that following skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, in an IL-17A-dependent manner. Kidney infiltrating neutrophils produced reactive oxygen species and their presence was associated with upregulation of endothelial adhesion molecules and inflammatory cytokines as well as the induction of kidney injury markers, including transient proteinuria. Neutrophils were responsible for inflammation and renal injury as demonstrated by experiments that inhibited neutrophil mobilization. Exploiting a mouse model containing photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin suggesting reverse transmigration. These findings demonstrate that neutrophils mediate transient kidney injury following skin exposure to UV light and, coupled with observations identifying similar neutrophil phenotypes in human lupus, could provide a mechanistic link to explain sun-induced systemic lupus flares.

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“…SLE is characterized by neutrophil subsets known as low-density granulocytes (LDGs). When compared to other immune cell subtypes, LDGs showed the highest expression of interferon gamma genes, CD10 with subpopulations that were speci cally positive correlation with disease severity and coronary patterns 44 .. In addition, neutrophils patterns were also described in the emerging COVID-19 infectious disease.…”

Section: Anticipated Resultsmentioning

confidence: 90%

A Protocol for Revealing Oral Neutrophil Heterogeneity by Single-Cell Immune Profiling in Human Saliva

Choudhury

Novotny

Aevermann

et al. 2020

Preprint

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Abstract Neutrophils are the most abundant white blood cells in the human body responsible for fighting viral, bacterial and fungi infections. Out of the 100 billion neutrophils produced daily, it is estimated that 10 % of these cells end up in oral biofluids. Because saliva is a fluid accessible through non-invasive techniques, it is an optimal source of cells and molecule surveillance in health and disease. While neutrophils are abundant in saliva, scientific advancements in neutrophil biology have been hampered likely due to their short life span, inability to divide once terminally differentiated, sensitivity to physical stress, and low RNA content. Here, we devise a protocol aiming to understand neutrophil heterogeneity by improving isolation methods, single-cell RNA extraction, sequencing and bioinformatic pipelines. Advanced flow cytometry 3D analysis, and machine learning validated our gating system model, by including positive neutrophil markers and excluding other immune cells and uncovered neutrophil heterogeneity. Considering specific cell markers, unique mitochondrial content, stringent and less stringent filtering strategies, our transcriptome single cell findings unraveled novel neutrophil subpopulations. Collectively, this methodology accelerates the discovery of salivary immune landscapes, with the promise of improving the understanding of diversification mechanisms, clinical diagnostics in health and disease, and guide targeted therapies.

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Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus

Cited by 192 publications

References 45 publications

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

A Protocol for Revealing Oral Neutrophil Heterogeneity by Single-Cell Immune Profiling in Human Saliva

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