Phagocytic Receptors Activate Syk and Src Signaling during Borrelia burgdorferi Phagocytosis

Killpack, Tess L.; Ballesteros, Maria; Bunnell, Stephen C.; Bedugnis, Alice; Kobzik, Lester; Hu, Linden T.; Petnicki‐Ocwieja, Tanja

doi:10.1128/iai.00004-17

Cited by 19 publications

(14 citation statements)

References 50 publications

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“…burgdorferi (Fig 8). The role played by Syk in the internalization of the spirochete confirms previous findings [16]. This signaling pathway is a positive regulator of the proinflammatory activity of macrophages, in contrast to CR3/CD14.…”

Section: Discussionsupporting

confidence: 89%

“…The common FcR γ-chain mediates Syk recruitment, which is responsible for downstream signaling activation. Since Syk silencing resulted in the loss of viability of RAW 264.7 cells, we proceeded to the chemical inhibition of the kinase with Piceatannol [16]. Both phagocytosis of B .…”

Section: Resultsmentioning

confidence: 99%

“…Other signaling pathways have been described to be involved in the internalization of B . burgdorferi , including Syk activation elicited by MARCO [16].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions

et al. 2019

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Macrophages mediate the elimination of pathogens by phagocytosis resulting in the activation of specific signaling pathways that lead to the production of cytokines, chemokines and other factors. Borrelia burgdorferi, the causative agent of Lyme disease, causes a wide variety of pro-inflammatory symptoms. The proinflammatory capacity of macrophages is intimately related to the internalization of the spirochete. However, most receptors mediating this process are largely unknown. We have applied a multiomic approach, including the proteomic analysis of B. burgdorferi-containing phagosome-enriched fractions, to identify surface receptors that are involved in the phagocytic capacity of macrophages as well as their inflammatory output. Sucrose gradient protein fractions of human monocyte-derived macrophages exposed to B. burgdorferi contained the phagocytic receptor, CR3/CD14 highlighting the major role played by these proteins in spirochetal phagocytosis. Other proteins identified in these fractions include C-type lectins, scavenger receptors or Siglecs, of which some are directly involved in the interaction with the spirochete. We also identified the Fc gamma receptor pathway, including the binding receptor, CD64, as involved both in the phagocytosis of, and TNF induction in response to B. burgdorferi in the absence of antibodies. The common gamma chain, FcγR, mediates the phagocytosis of the spirochete, likely through Fc receptors and C-type lectins, in a process that involves Syk activation. Overall, these findings highlight the complex array of receptors involved in the phagocytic response of macrophages to B. burgdorferi.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions

et al. 2019

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“…We have also discovered that Src is involved with many immune related processes, such as actin organization and endocytosis functions. Src family tyrosine kinases were reported to contribute to the phagocytosis and cytokine activation after Borrelia burgdorferi infection (Killpack et al 2017 ). Src family kinases were responsible for signal transduction in immune cells, acting as immunoreceptors, cytokine receptors and integrin receptors.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomics revealed modulation of macrophages by MetQ gene of Streptococcus suis serotype 2

Pei

Liu

et al. 2020

AMB Expr

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Streptococcus suis serotype 2 (SS2) is a serious zoonotic pathogen; it can lead to symptoms of streptococcal toxic shock syndrome (STSS) in humans and sepsis in pigs, and poses a great threat to public health. The SS2 MetQ gene deletion strain has attenuated antiphagocytosis, although the mechanism of antiphagocytosis and pathogenesis of MetQ in SS2 has remained unclear. In this study, stable isotope labeling by amino acids in cell culture (SILAC) based liquid chromatography–mass spectrometry (LC–MS) and subsequent bioinformatics analysis was used to determine differentially expressed proteins of RAW264.7 cells infected with △MetQ and ZY05719. Proteomic results were verified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting for selected proteins. Further research was focused mainly on immune system processes related to downregulated proteins, such as Src and Ccl9, and actin cytoskeleton and endocytosis related upregulated proteins, like Pstpip1 and Ppp1r9b. The proteomic results in this study shed light on the mechanism of antiphagocytosis and innate immunity of macrophages infected with △MetQ and ZY05719, which might provide novel targets to prevent or control the infection of SS2.

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“…This could possibly be due to the later time point we selected for sequencing. It has also been shown that spleen tyrosine kinase (Syk) has an important role in phagocytosis of Bb via integrin binding (76). The Syk gene ( Syk ) is significantly upregulated in an MyD88-dependent manner, suggesting that MyD88 drives over-expression of Syk to increase phosphorylation and activation of proteins involved in generating actin branches.…”

Section: Discussionmentioning

confidence: 99%

Macrophage mediated recognition and clearance ofBorrelia burgdorferinelicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation

Benjamin¹,

Hawley²,

Vera-Licona³

et al. 2019

Preprint

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35Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi (Bb). It 36 is believed that the robust inflammatory response induced by the host's innate immune 37 system is responsible for the clinical manifestations associated with Bb infection. The 38 macrophage plays a central role in the immune response to many bacterial infections and 39 is thought to play a central role in activation of the innate immune response to Bb. 40 Previous studies have shown that following phagocytosis of spirochetes by macrophages, 41 phagosome maturation results in degradation of Bb and liberation of bacterial lipoproteins 42 and nucleic acids, which are recognized by TLR2 and TLR8, respectively, and elicit 43MyD88-mediated phagosome signaling cascades. Bone marrow-derived macrophages 44 (BMDMs) from MyD88 -/mice show significantly reduced spirochete uptake and 45 inflammatory cytokine production when incubated with Bb ex vivo. Paradoxically, 46additional studies revealed that Bb-infected MyD88 -/mice exhibit inflammation in joint 47 and heart tissues. To determine the contribution of MyD88 to macrophage-mediated 48 spirochete clearance, we compared wildtype (WT) and MyD88 -/mice using a murine 49 model of Lyme disease. MyD88 -/mice showed increased Bb burdens in hearts 28 days 50 post infection, while H&E staining and immunohistochemistry showed significantly 51 increased inflammation and greater macrophage infiltrate in the hearts of MyD88 -/mice. 52This suggests that Bb triggers MyD88-independent inflammatory pathways in 53 macrophages to facilitate cell recruitment to tissues. Upon stimulation with Bb ex vivo, 54WT and MyD88 -/-BMDMs exhibit significant differences in bacteria uptake, suggesting 55 that MyD88 signaling mediates cytoskeleton remodeling and the formation of membrane 56 protrusions to enhance bacteria phagocytosis. A comprehensive transcriptome 57 comparison in Bb-infected WT and MyD88 -/-BMDMs identified a large cohort of MyD88-58 dependent genes that are differentially expressed in response to Bb, including genes 59 involved in actin and cytoskeleton organization (Daam1, Fmnl1). We also identified a 60 cohort of differentially-expressed MyD88-independent chemokines (Cxcl2, Ccl9) known 61 to recruit macrophages. We identified master regulators and generated networks which 62 model potential signaling pathways that mediate both phagocytosis and the inflammatory 63 AUTHOR SUMMARY 67Macrophages play prominent roles in bacteria recognition and clearance, including 68Borrelia burgdorferi (Bb), the Lyme disease spirochete. To elucidate mechanisms by 69 which MyD88/TLR signaling enhances clearance of Bb by macrophages, we studied Bb-70 infected wildtype (WT) and MyD88-/-mice and Bb-stimulated bone marrow-derived 71 macrophages (BMDMs). Bb-infected MyD88-/-mice show increased bacterial burdens, 72 macrophage infiltration and altered gene expression in inflamed heart tissue. MyD88-/-73 BMDMs exhibit impaired uptake of spirochetes but comparable maturation of 74 phagosomes following internaliza...

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Phagocytic Receptors Activate Syk and Src Signaling during Borrelia burgdorferi Phagocytosis

Cited by 19 publications

References 50 publications

Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions

Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions

Quantitative proteomics revealed modulation of macrophages by MetQ gene of Streptococcus suis serotype 2

Macrophage mediated recognition and clearance ofBorrelia burgdorferinelicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation

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