A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling, 2023, Hackney et al.

[SNT Gatchaman]

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

Spoiler: Multiple authors

Jason A. Hackney; Haridha Shivram; Jason Vander Heiden; Chris Overall; Luz Orozco; Xia Gao; Eugene Kim; Nathan West; Aditi Qamra; Diana Chang; Arindam Chakrabarti; David F. Choy; Alexis J. Combes; Tristan Courau; Gabriela K. Fragiadakis; Arjun Arkal Rao; Arja Ray; Jessica Tsui; Kenneth Hu; Nicholas F. Kuhn; Matthew F. Krummel; David J. Erle; Kirsten Kangelaris; Aartik Sarma; Zoe Lyon; Carolyn S. Calfee; Prescott G. Woodruff; Rajani Ghale; Eran Mick; Ashley Byrne; Beth Shoshana Zha; Charles Langelier; Carolyn M. Hendrickson; Monique G.P. van der Wijst; George C. Hartoularos; Tianna Grant; Raymund Bueno; David S. Lee; John R. Greenland; Yang Sun; Richard Perez; Anton Ogorodnikov; Alyssa Ward; Chun Jimmie Ye; Yumiko Abe-Jones; Michael Adkisson; K. Mark Ansel; Saurabh Asthana; Alexander Beagle; Sharvari Bhide; Cathy Cai; Saharai Caldera; Maria Calvo; Sidney A. Carrillo; Suzanna Chak; Stephanie Christenson; Zachary Collins; Spyros Darmanis; Angela Detweiler; Catherine DeVoe; Walter Eckalbar; Jeremy Giberson; Ana Gonzalez; Gracie Gordon; Paula Hayakawa Serpa; Alejandra Jauregui; Chayse Jones; Serena Ke; Divya Kushnoor; Tasha Lea; Deanna Lee; Aleksandra Leligdowicz; Yale Liu; Salman Mahboob; Lenka Maliskova; Michael Matthay; Elizabeth McCarthy; Priscila Muñoz-Sandoval; Norma Neff; Viet Nguyen; Nishita Nigam; Randy Parada; Maira Phelps; Logan Pierce; Priya Prasad; Sadeed Rashid; Gabriella Reeder; Nicklaus Rodriguez; Bushra Samad; Andrew Schroeder; Cole Shaw; Alan Shen; Austin Sigman; Pratik Sinha; Matthew Spitzer; Sara Sunshine; Kevin Tang; Luz Torres Altamirano; Alexandra Tsitsiklis; Erden Tumurbaatar; Vaibhav Upadhyay; Alexander Whatley; Andrew Willmore; Michael Wilson; Juliane Winkler; Kristine Wong; Kimberly Yee; Michelle Yu; Mingyue Zhou; Wandi S. Zhu; Thiru Ramalingam; Jacqueline M. McBride; Fang Cai; Anastasia Teterina; Min Bao; Larry Tsai; Ivan O. Rosas; Aviv Regev; Sharookh B. Kapadia; Rebecca N. Bauer; Carrie M. Rosenberger

Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression.

This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.


Link | PDF (iScience)

 

[Kitty]

They'll soon be discovering that the EN-RAGE gene is upregulated in middle-aged women, mark my words.

 

[SNT Gatchaman]

On EN-RAGE (extracellular newly identified receptor for advanced glycation end products) —

This study supports a working model whereby IL-6 differentiates myeloid cells from both monocytic and granulocytic lineages to a suppressive phenotype characterized by low antigen presentation on HLA-DR and increased expression of multiple factors that can suppress T cells (IL-10, PD-L1, and TGF-b1). We define a pan-myeloid EN-RAGE program of coordinately expressed genes in the airways and blood of COVID-19 patients that is prognostic for severe outcomes and is robust across 7 cohorts.

EN-RAGEhi cells express multiple phenotypic hallmarks of MDSCs [myeloid-derived suppressor cells] by cell surface protein analysis: decreased capacity for antigen presentation and costimulation through HLA-DR and CD40, and increased potential to suppress T cells through PD-L1. This was associated with sustained elevated expression of markers on T cells dysfunction such as PD-1 in patients with prolonged mechanical ventilation or who died.

COVID-19 patients with higher EN-RAGE signature expression had a greater risk of future mechanical ventilation and mortality, and ENRAGEhi myeloid cell impairment of optimal T cell-mediated immunity is one potential mechanism. EN-RAGEhi cells also express genes that can increase or skew inflammation or promote lung barrier permeability (i.e., S100A12, IL-1b, and TGF-b1), consistent with MDSCs expressing both pro- and anti-inflammatory genes.

A potential connection between EN-RAGEhi myeloid cells and NK cells or the suppressive regulatory T cell phenotype observed in severe COVID-19 patients remains to be characterized.

COVID-19 and cancer share risk factors, such as age and metabolic syndrome, and underlying immunobiology, such as MDSCs and T cell dysfunction, making it appealing to speculate that EN-RAGEhi myeloid cells may contribute to pathology in multiple diseases.

 

[SNT Gatchaman]

Note that EN-RAGE was one of the distinct proposed biomarkers in Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study (2022, Nature Communications)

(In that paper fatigue was considered a neuro symptom, but we'll let that slide.)

Class I was defined by absent/mild NS [neuro symptoms], including headache, dizziness, anosmia and ageusia. Class II encompassed moderate NS, including fatigue, acute peripheral neuropathy and myopathy, whereas class III was specified by severe NS, including seizures, stroke or intracranial hemorrhage, encephalopathy, coma or death.

They compared class I to III with HCs and non-covid relate neuroinflammatory controls. EN-RAGE separate class II and III from healthy and inflammatory controls.

EN-RAGE (class III vs. I: p = 0.003, class III vs. infl. ctrl: p = 0.0002)