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Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19.

Publication ,  Journal Article
Grant, RA; Poor, TA; Sichizya, L; Diaz, E; Bailey, JI; Soni, S; Senkow, KJ; Pérez-Leonor, XG; Abdala-Valencia, H; Lu, Z; Donnelly, HK ...
Published in: JCI Insight
March 19, 2024

BACKGROUNDSurvivors of pneumonia, including SARS-CoV-2 pneumonia, are at increased risk for cognitive dysfunction and dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the systemic release of lung-derived pro-inflammatory cytokines. Microglia are poised to respond to inflammatory signals from the circulation, and their dysfunction has been linked to cognitive impairment in murine models of dementia and in humans.METHODSWe measured levels of 55 cytokines and chemokines in bronchoalveolar lavage fluid and plasma from 341 patients with respiratory failure and 13 healthy controls, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. We used flow cytometry to sort neuroimmune cells from postmortem brain tissue from 5 patients who died from COVID-19 and 3 patients who died from other causes for single-cell RNA-sequencing.RESULTSMicroglia from patients with COVID-19 exhibited a transcriptomic signature suggestive of their activation by circulating pro-inflammatory cytokines. Peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, but cumulative cytokine exposure was higher in patients with COVID-19. Treatment with corticosteroids reduced expression of COVID-19-specific cytokines.CONCLUSIONProlonged lung inflammation results in sustained elevations in circulating cytokines in patients with SARS-CoV-2 pneumonia compared with those with pneumonia secondary to other pathogens. Microglia from patients with COVID-19 exhibit transcriptional responses to inflammatory cytokines. These findings support data from rodent models causally linking systemic inflammation with cognitive dysfunction in pneumonia and support further investigation into the role of microglia in pneumonia-related cognitive dysfunction.FUNDINGSCRIPT U19AI135964, UL1TR001422, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, T32HL076139.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 19, 2024

Volume

9

Issue

8

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Pneumonia
  • Microglia
  • Mice
  • Lung
  • Interleukin-1beta
  • Humans
  • Fluorescent Antibody Technique
  • Cytokines
  • Cognitive Dysfunction
 

Citation

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Grant, R. A., Poor, T. A., Sichizya, L., Diaz, E., Bailey, J. I., Soni, S., … Northwestern University Successful Clinical Response In Pneumonia Therapy (NU SCRIPT) Investigators. (2024). Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19. JCI Insight, 9(8). https://doi.org/10.1172/jci.insight.178859
Grant, Rogan A., Taylor A. Poor, Lango Sichizya, Estefani Diaz, Joseph I. Bailey, Sahil Soni, Karolina J. Senkow, et al. “Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19.JCI Insight 9, no. 8 (March 19, 2024). https://doi.org/10.1172/jci.insight.178859.
Grant RA, Poor TA, Sichizya L, Diaz E, Bailey JI, Soni S, et al. Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19. JCI Insight. 2024 Mar 19;9(8).
Grant, Rogan A., et al. “Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19.JCI Insight, vol. 9, no. 8, Mar. 2024. Pubmed, doi:10.1172/jci.insight.178859.
Grant RA, Poor TA, Sichizya L, Diaz E, Bailey JI, Soni S, Senkow KJ, Pérez-Leonor XG, Abdala-Valencia H, Lu Z, Donnelly HK, Simons LM, Ozer EA, Tighe RM, Lomasney JW, Wunderink RG, Singer BD, Misharin AV, Budinger GRS, Northwestern University Successful Clinical Response In Pneumonia Therapy (NU SCRIPT) Investigators. Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19. JCI Insight. 2024 Mar 19;9(8).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 19, 2024

Volume

9

Issue

8

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Pneumonia
  • Microglia
  • Mice
  • Lung
  • Interleukin-1beta
  • Humans
  • Fluorescent Antibody Technique
  • Cytokines
  • Cognitive Dysfunction