Interleukin-1- Receptor Kinase 4 Inhibition: Achieving Immunomodulatory Synergy to Mitigate the Impact of COVID-19

Gupta, Akash; Chun, Hyung J.

doi:10.3389/fimmu.2021.693085

Cited by 4 publications

(2 citation statements)

References 24 publications

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“…Additionally, we highlight different molecular subsets of neutrophils in smoke-exposed animals that were identified as important inflammatory amplifiers. Finally, we provide first proof-of-principle evidence that pharmacological inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4), a central signaling node located down-stream of TLR and IL-1 receptor family members ( 23 ), reduces neutrophil and MoAM recruitment and diminishes smoke-induced inflammation.…”

Section: Introductionmentioning

confidence: 99%

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling

Wohnhaas,

Baßler,

Watson

et al. 2024

Front. Immunol.

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Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling.

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Section: Introductionmentioning

confidence: 99%

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling

Wohnhaas,

Baßler,

Watson

et al. 2024

Front. Immunol.

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show abstract

“…IRAK4-inactive knock-in mice were completely resistant to LPS- and CpG-induced shock [31] . Given that the cytokine activation pattern of COVID-CRS largely overlaps with the cytokines regulated by IRAK4, some researchers have speculated that IRAK4 is a potential treatment target for COVID-19 patients with systemic inflammation [32] , [33] .…”

Section: Introductionmentioning

confidence: 99%

Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome

Yin

et al. 2022

Biomedicine & Pharmacotherapy

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Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics

Gupta

Savytskyi

Coban

et al. 2023

Molecular Aspects of Medicine

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Interleukin-1- Receptor Kinase 4 Inhibition: Achieving Immunomodulatory Synergy to Mitigate the Impact of COVID-19

Cited by 4 publications

References 24 publications

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling

Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome

Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics

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