Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation

Ryzhakov, Grigory; Almuttaqi, Hannah; Corbin, Alastair; Berthold, Dorothée L.; Khoyratty, Tariq E.; Eames, Hayley L.; Bullers, Samuel J.; Pearson, Claire; Ai, Zhichao; Zec, Kristina; Bonham, Sarah; Fischer, Román; Jostins-Dean, Luke; Travis, Simon; Kessler, Benedikt M.; Udalova, Irina A.

doi:10.1038/s41467-021-27038-5

Cited by 22 publications

(16 citation statements)

References 67 publications

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“…IRF5 can be phosphorylated by several kinases including TAK1, IKKβ, and Pyk2 73 . In the absence of CXCL4 costimulation, TLR8-induced activation of IRF5 is mediated by TAK1 and IKKβ, with a minor role for TBK1 14 , 64 ; these kinases can phosphorylate IRF5 and/or its upstream adapter TASL.…”

Section: Discussionmentioning

confidence: 99%

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

Bachu

Brauner

et al. 2022

Nat Commun

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Regulation of endosomal Toll-like receptor (TLR) responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases, with CXCL4 proposed to potentiate TLR responses by binding to nucleic acid TLR ligands and facilitating their endosomal delivery. Here we report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively amplifying inflammatory gene transcription and interleukin (IL)−1β production, while partially attenuating the interferon response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activates TBK1 and IKKε, repurposes these kinases towards an inflammatory response via coupling with IRF5, and activates the NLRP3 inflammasome. CXCL4 signaling, in a cooperative and synergistic manner with TLR8, induces chromatin remodeling and activates de novo enhancers associated with inflammatory genes. Our findings thus identify new regulatory mechanisms of TLR responses relevant for cytokine storm, and suggest targeting the TBK1-IKKε-IRF5 axis may be beneficial in inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

Bachu

Brauner

et al. 2022

Nat Commun

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“…[ 16 , 19 , 47 , 58 ] Other studies demonstrated its effects on secretion of proinflammatory cytokines from macrophages, such as IL‐1 β and IL‐18 [ 59 ] or IL‐6, TNF ‐α , and IL‐12. [ 60 ] Interestingly, PYK2 was found to regulate inflammatory response in the gut via direct binding and phosphorylation of IRF5 (Interferon regulating factor 5). [ 60 ] Here we show that PYK2 ablation inhibits CCL2 secretion by BC cells (Figure 3D,E ) and CCR2 expression in macrophages (Figure 6E, G, I ), thereby impairing CCL2–CCR2 signaling and consequently TAM recruitment.…”

Section: Discussionmentioning

confidence: 99%

“…[ 60 ] Interestingly, PYK2 was found to regulate inflammatory response in the gut via direct binding and phosphorylation of IRF5 (Interferon regulating factor 5). [ 60 ] Here we show that PYK2 ablation inhibits CCL2 secretion by BC cells (Figure 3D,E ) and CCR2 expression in macrophages (Figure 6E, G, I ), thereby impairing CCL2–CCR2 signaling and consequently TAM recruitment. Indeed, previous reports demonstrated the inhibitory effects of CCL2 neutralizing antibodies on breast cancer growth, metastasis, and TAM recruitment.…”

Section: Discussionmentioning

confidence: 99%

Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis

et al. 2022

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Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. By using different genetic mouse models, the authors show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or in both, markedly reduces the number of infiltrating tumor macrophages and concomitantly inhibits tumor angiogenesis and tumor growth. Strikingly, PYK2 ablation only in macrophages is sufficient to induce similar effects. These phenotypic changes are associated with reduced monocyte recruitment and a substantial decrease in tumor‐associated macrophages (TAMs). Mechanistically, the authors show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibits Notch1 signaling and consequently reduces CCL2 secretion by breast cancer cells, and concurrently reduces the levels of CCR2, CXCR4, IL‐4Rα, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization, and tumor angiogenesis. The expression of PYK2 is correlated with infiltrated macrophages in breast cancer patients, and its effects on macrophage infiltration and pro‐tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy.

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“…IRF5 can be phosphorylated by several kinases including TAK1, IKKβ and Pyk2 72 . In the absence of CXCL4 costimulation, TLR8-induced activation of IRF5 is mediated by TAK1 and IKKβ, with a minor role for TBK1 14, 63 ; these kinases can phosphorylate IRF5 and/or its upstream adaptor TASL.…”

Section: Discussionmentioning

confidence: 99%

Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

Bachu

Brauner

et al. 2022

Preprint

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Regulation of endosomal TLR responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases. The current paradigm is that CXCL4 potentiates TLR responses by binding and facilitating endosomal delivery of nucleic acid TLR ligands. We report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively and dramatically amplifying inflammatory gene transcription and IL-1beta; production, while partially attenuating the IFN response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activated TBK1/IKKε; and repurposed these kinases towards an inflammatory response via coupling with IRF5, and by activating the NLRP3 inflammasome without the need for an exogenous activator of a second signal for IL-1beta; maturation. CXCL4 signaling strongly induced chromatin remodeling and de novo enhancers associated with inflammatory genes in a cooperative and synergistic manner with TLR8. These findings identify new mechanisms of regulation of TLR responses relevant for cytokine storm, and suggest targeting the TBK1/IKKε;-IRF5 axis may be beneficial in inflammatory diseases.

show abstract

Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation

Cited by 22 publications

References 67 publications

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

Mouse Modeling Dissecting Macrophage–Breast Cancer Communication Uncovered Roles of PYK2 in Macrophage Recruitment and Breast Tumorigenesis

Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

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