Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions

Sawant, Kirti V.; Poluri, Krishna Mohan; Dutta, Amit K.; Sepuru, Krishna Mohan; Troshkina, Anna; Garofalo, Roberto P.; Rajarathnam, Krishna

doi:10.1038/srep33123

Cited by 232 publications

(192 citation statements)

References 37 publications

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“…It is likely that the absence of chemical shift changes is due to cancellation between contributions from direct and indirect interactions of similar magnitude but opposite sign. Lack of CSP of lysine residues involved in GAG binding has been previously observed in other chemokines [46,47,48,49]. Our docking model and CSP data collectively indicate that hydrophobic packing, guided by H-bonding and ionic interactions, mediates Site-I binding.…”

Section: Resultssupporting

confidence: 80%

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Brown

Sepuru

Rajarathnam

2017

IJMS

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CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family.

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Section: Resultssupporting

confidence: 80%

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Brown

Sepuru

Rajarathnam

2017

IJMS

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“…The chemokine IL‐8 participates directly in the initial inflammatory phase by acting as a potent chemoattractant . Together with CXCL8 , stimulation with T. benhamiae DSM 6916 led to high expression of CXCL1 , another chemokine playing a dual role in the host immune response by recruiting and activating neutrophils to combat infection . This is the first time a stimulation of CXCL1 chemokine production by T .…”

Section: Discussionmentioning

confidence: 86%

Innate immune response of human epidermal keratinocytes and dermal fibroblasts to in vitro incubation of Trichophyton benhamiae DSM 6916

Hesse-Macabata

Morgner

Morgenstern

et al. 2019

Acad Dermatol Venereol

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Background Superficial cutaneous infection caused by the zoophilic dermatophyte Trichophyton benhamiae is often associated with a highly inflammatory immune response. As non‐professional immune cells, epidermal keratinocytes and dermal fibroblasts contribute to the first line of defence by producing pro‐inflammatory cytokines and antimicrobial peptides (AMP). Objective Purpose of this study was to gain a deeper understanding of the pathogenesis and the fungal–host interaction as not much is known about the innate immune response of these cutaneous cells against T. benhamiae. Methods Using a dermatophytosis model of fibroblasts and keratinocytes incubated with T. benhamiae DSM 6916, analyses included determination of cell viability and cytotoxicity, effects on the innate immune response including expression and secretion of pro‐inflammatory cytokines/chemokines and expression of AMP, as well as alterations of genes involved in cell adhesion. Results Trichophyton benhamiae DSM 6916 infection led to severe cell damage and direct induction of a broad spectrum of pro‐inflammatory cytokines and chemokines in both cutaneous cells. Only keratinocytes differentially up‐regulated AMP genes expression after T. benhamiae DSM 6916 infection. Expression of AMPs in fibroblasts was not inducible by fungal infection, whereas their absences potentially contributed to a continuous increase in the fungal biomass on fibroblasts, which in turn was reduced in keratinocytes possibly due to the antimicrobial actions of induced AMPs. On mRNA level, T. benhamiae DSM 6916 infection altered cell–cell contact proteins in keratinocytes, indicating that targeting specific cell–cell adhesion proteins might be part of dermatophytes’ virulence strategy. Conclusion This study showed that in addition to immune cells, keratinocytes and fibroblasts could participate in antimicrobial defence against an exemplary infection with T. benhamiae DSM 6916.

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“…6B). CXCL-1 (also known as KC in mice) plays a pivotal role in recruiting and activating neutrophils at tissue sites [29]. This is relevant because we observed considerable neutrophil infiltration in the kidneys of nephritic Mer-KO mice [18].…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Mer receptor tyrosine kinase inhibition of glomerular endothelial cell inflammation

Zhen

Finkelman

Shao

2018

Journal of Leukocyte Biology

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Endotoxin induces a variety of proinflammatory mediators and plays a crucial role in kidney inflammation. The receptor tyrosine kinase, Mer, diminishes renal inflammation by attenuating inflammatory responses. We previously reported that Mer is predominantly expressed on glomerular endothelial cells (GECs) and that Mer deficiency is associated with increased renal inflammation when mice are challenged with nephrotoxic serum. We consequently hypothesized that Mer signaling down-regulates LPS-driven inflammatory responses in GECs. To test this hypothesis, primary GECs were isolated from the kidneys of Mer-KO and wild-type (WT) control mice. LPS treatment induced Akt and STAT3 activation along with Bcl-xl up-regulation in WT GECs; these responses were all increased in Mer-deficient GECs. In addition, STAT1 and ERK1/2 up-regulation and activation were observed in Mer-KO GECs exposed to LPS. In contrast, expression of the inhibitory signaling molecule, suppressor of cytokine signaling-3 (SOCS-3), was much higher in LPS-stimulated WT than Mer-deficient GECs. Deficiency of Mer was also associated with significantly increased NF-κB expression and activation. These observations indicate that Mer functions as an intrinsic feedback inhibitor of inflammatory mediator-driven immune responses in GECs during kidney injury and suggest a new therapeutic strategy for glomerular diseases.

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Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions

Cited by 232 publications

References 37 publications

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Innate immune response of human epidermal keratinocytes and dermal fibroblasts to in vitro incubation of Trichophyton benhamiae DSM 6916

Mechanism of Mer receptor tyrosine kinase inhibition of glomerular endothelial cell inflammation

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