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

Bachu, Mahesh; Du, Yong; Brauner, Caroline; Yuan, Ruoxi; Kioon, Marie Dominique Ah; Chesi, Giancarlo; Barrat, Franck J.; Ivashkiv, Lionel B.

doi:10.1038/s41467-022-31132-7

Cited by 22 publications

(47 citation statements)

References 89 publications

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“…PBMCs were prepared using Ficoll-Paque density gradient (GE Healthcare) as previously described ( 78 ). pDCs and monocytes were isolated from PBMCs by positive selection using BDCA4-conjugated ( 78 ) and CD14-conjugated ( 79 ) microbeads (Miltenyi Biotec), respectively. pDC-depleted PBMCs were prepared by removing BDCA4-positve cells from PBMCs using microbeads (Miltenyi Biotec).…”

Section: Methodsmentioning

confidence: 99%

Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19

et al. 2022

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Lung-infiltrating macrophages create a marked inflammatory milieu in a subset of patients with COVID-19 by producing a cytokine storm, which correlates with increased lethality. However, these macrophages are largely not infected by SARS-CoV-2, so the mechanism underlying their activation in the lung is unclear. Type I interferons (IFN-I) contribute to protecting the host against SARS-CoV-2 but may also have some deleterious effect, and the source of IFN-I in the lungs of infected patients is not well defined. Plasmacytoid dendritic cells (pDCs), a key cell type involved in antiviral responses, can produce IFN-I in response to SARS-CoV-2. We observed the infiltration of pDCs in the lungs of SARS-CoV-2–infected patients, which correlated with strong IFN-I signaling in lung macrophages. In patients with severe COVID-19, lung macrophages expressed a robust inflammatory signature, which correlated with persistent IFN-I signaling at the single-cell level. Hence, we observed the uncoupling in the kinetics of the infiltration of pDCs in the lungs and the associated IFN-I signature, with the cytokine storm in macrophages. We observed that pDCs were the dominant IFN-α–producing cells in response to the virus in the blood, whereas macrophages produced IFN-α only when in physical contact with infected epithelial cells. We also showed that IFN-α produced by pDCs, after the sensing of SARS-CoV-2 by TLR7, mediated changes in macrophages at both transcriptional and epigenetic levels, which favored their hyperactivation by environmental stimuli. Together, these data indicate that the priming of macrophages can result from the response by pDCs to SARS-CoV-2, leading to macrophage activation in patients with severe COVID-19.

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Section: Methodsmentioning

confidence: 99%

Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19

et al. 2022

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“…Several groups including ours have reported activation of inflammatory signaling pathways and chromatin remodeling at inflammatory genes in myeloid cells after stimulation with CXCL4 alone, in the absence of exogenous nucleic acids 1, 10,12,14,18 . This suggests that CXCL4 can also activate myeloid cells independently of its NA-chaperone properties.…”

Section: Mainmentioning

confidence: 77%

“…CXCL4 alone substantially activates NF-κB and MAPKs p38 and ERK, and also activates TBK1 12 . We next investigated the role of these signaling molecules in induction of representative inflammatory and fibrotic genes, and the neutrophil chemokines CXCL1 and CXCL2.…”

Section: Nf-κb and A Tbk1-jnk Axis Drive Inflammatory Fibrotic And Ne...mentioning

confidence: 99%

“…As inhibition of TBK1 does not diminish NF-κB activation 12 , we tested whether TBK1 regulates MAPK signaling. In addition to activating ERK and p38 12 , CXCL4 activated MAPK JNK p46 and p54 isoforms, and this activation was suppressed when TBK1 was inhibited (Fig. 2c).…”

Section: Nf-κb and A Tbk1-jnk Axis Drive Inflammatory Fibrotic And Ne...mentioning

confidence: 99%

“…TLR3 is minimally expressed in human macrophages 44 and stimulation of human macrophages with the TLR3 ligand poly (I:C) does not induce gene expression 12 . Thus, despite the differences between CXCL4 and LPS responses described above, we tested whether TLR4 is involved in CXCL4 responses in human macrophages.…”

Section: Cxcl4 Signaling and Gene Activation Involve Tlr4mentioning

confidence: 99%

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CXCL4 signaling and gene induction in human monocytes involve a TLR4 response divergent from LPS

Yuan

Mishra

Bell

et al. 2022

Preprint

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The chemokine CXCL4 activates myeloid cells and contributes to the pathogenesis of inflammatory and fibrotic diseases. One mechanism of CXCL4 action is binding of nucleic acids to promote their internalization and activation of endosomal TLRs. However, the signaling pathways and receptors that mediate myeloid cell responses to CXCL4 alone are not well characterized. Here, we report that in primary human monocytes, CXCL4 activated NF-kB and a TBK1-JNK signaling axis that drive the expression of inflammatory, fibrotic and neutrophil chemokine genes, and also RIPK3-dependent necroptosis. Surprisingly, six distinct lines of evidence targeting TLR4 expression and function suggested a role for TLR4 in CXCL4 responses. However, in contrast to the canonical TLR4 agonist LPS, CXCL4 did not effectively activate an autocrine IFN response or IL-12 family genes, even after IFN-b; priming of monocytes. In accord with its role in inducing chemokine and inflammatory gene expression, CXCL4 regulated neutrophil and macrophage infiltration into skin wounds, and promoted wound healing in a mouse model. Our findings suggest that CXCL4 modulates the profile of TLR4 responses to induce a macrophage phenotype divergent from LPS-activated cells, provide new insights into mechanisms by which CXCL4 activates human monocytes, and implicate CXCL4 in regulation of skin wound healing.

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Staphyloccocus aureus biofilm, in absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune‐suppressive genes in human monocytes

Bell,

Cann,

Mishra

et al. 2024

Journal Orthopaedic Research

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Staphyloccocus aureus (S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI). S. aureus forms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic‐tolerant metabolic state. We developed an in vitro system to study S. aureus biofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data, S. aureus biofilm induced expression of inflammatory genes such as TNF and IL1B, and their anti‐inflammatory counter‐regulator IL10. S. aureus biofilm also activated expression of PD‐1 ligands, and IL‐1RA, molecules that have the potential to suppress T cell function or differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm‐encased bacteria that was heat resistant and >3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak kinase inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita‐pathogen‐associated molecular pattern, a molecule that signals microbial viability. Induction of T cell suppressive genes by S. aureus biofilm provides insights into mechanisms that can suppress T cell immunity in PJI.

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

Cited by 22 publications

References 89 publications

Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19

Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19

CXCL4 signaling and gene induction in human monocytes involve a TLR4 response divergent from LPS

Staphyloccocus aureus biofilm, in absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune‐suppressive genes in human monocytes

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