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

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)

 

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

 

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

 

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.)

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.