Cell type‐specific mechanisms coupling protease‐activated receptor‐1 to infectious colitis pathogenesis

Boucher, Alexander A.; Rosenfeldt, Leah; Mureb, Duaa; Shafer, Jessica; Sharma, Bal Krishan; Lane, Adam; Crowther, Rebecca R.; McKell, Melanie C; Whitt, Jordan; Alenghat, Theresa; Qualls, Joseph E.; Antoniak, Silvio; Mackman, Nigel; Flick, Matthew J.; Steinbrecher, Kris A.; Palumbo, Joseph S.

doi:10.1111/jth.14641

Cited by 12 publications

(15 citation statements)

References 55 publications

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“…Furthermore, the functions of PARs show cell/tissue specific mechanisms. Boucher et al [ 44 ] demonstrate that myeloid-associated PAR1 promotes while intestinal epithelial associated PAR1 limits mucosal damage in C. rodentium-induced colitis in mice. The physiologic outcomes of PAR1/2 activation/inhibition therefore not only depend on specific agonist/ligand activation mode, but also cell type and the interaction with other receptors [ 37 , 38 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Activated Protein C Protects against Murine Contact Dermatitis by Suppressing Protease-Activated Receptor 2

Lin

Zhao

Fryer

et al. 2022

IJMS

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Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with excessive inflammation and defective skin barrier function. Activated protein C (APC) is a natural anticoagulant with anti-inflammatory and barrier protective functions. However, the effect of APC on AD and its engagement with protease activated receptor (PAR)1 and PAR2 are unknown. Methods: Contact hypersensitivity (CHS), a model for human AD, was induced in PAR1 knockout (KO), PAR2KO and matched wild type (WT) mice using 2,4-dinitrofluorobenzene (DNFB). Recombinant human APC was administered into these mice as preventative or therapeutic treatment. The effect of APC and PAR1KO or PARKO on CHS was assessed via measurement of ear thickness, skin histologic changes, inflammatory cytokine levels, Th cell phenotypes and keratinocyte function. Results: Compared to WT, PAR2KO but not PAR1KO mice displayed less severe CHS when assessed by ear thickness; PAR1KO CHS skin had less mast cells, lower levels of IFN-γ, IL-4, IL-17 and IL-22, and higher levels of IL-1β, IL-6 and TGF-β1, whereas PAR2KO CHS skin only contained lower levels of IL-22 and IgE. Both PAR1KO and PAR2KO spleen cells had less Th1/Th17/Th22/Treg cells. In normal skin, PAR1 was present at the stratum granulosum and spinosum, whereas PAR2 at the upper layers of the epidermis. In CHS, however, the expression of PAR1 and PAR2 were increased and spread to the whole epidermis. In vitro, compared to WT cells, PAR1KO keratinocytes grew much slower, had a lower survival rate and higher para permeability, while PAR2KO cells grew faster, were resistant to apoptosis and para permeability. APC inhibited CHS as a therapeutic but not as a preventative treatment only in WT and PAR1KO mice. APC therapy reduced skin inflammation, suppressed epidermal PAR2 expression, promoted keratinocyte growth, survival, and barrier function in both WT and PAR1KO cells, but not in PAR2KO cells. Conclusions: APC therapy can mitigate CHS. Although APC acts through both PAR1 and PAR2 to regulate Th and mast cells, suppression of clinical disease in mice is achieved mainly via inhibition of PAR2 alone. Thus, APC may confer broad therapeutic benefits as a disease-modifying treatment for AD.

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Section: Discussionmentioning

confidence: 99%

Activated Protein C Protects against Murine Contact Dermatitis by Suppressing Protease-Activated Receptor 2

Lin

Zhao

Fryer

et al. 2022

IJMS

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“…Adult PAR1 ‐/‐ (ΔPAR1) and wild‐type (WT, PAR1 +/+ ) mice, maintained as cousin lines, were used for this study 29 . We generated a series of mouse lines in which PAR1 was deleted in various cell types by crossing mice with a floxed PAR1 allele (PAR1 fl/fl ) 30 with various mouse lines expressing Cre in a cell type‐specific manner: deletion in lung EpCs (PAR1 fl/fl ;SPC Cre [PAR1ΔEpC] mice 31 ), deletion in hematopoietic and EC (PAR1 fl/fl ;Tie2 Cre [PAR1ΔHEC] 31 ), deletion in myeloid cells (PAR1 fl/fl ;LysM Cre [PAR1ΔMy] 31 ), and deletion in ECs (PAR1 fl/fl ;VECad Cre‐ERT2 [PAR1ΔEC]) 32 . To activate VECad Cre‐ERT2 expression, 8‐week‐old PAR1 fl/fl ;VECad Cre‐ERT2 mice were gavaged with 2 mg of tamoxifen (Sigma‐Aldrich, St. Louis, MO) dissolved in corn oil for 5 consecutive days and then mice were used 5 days later.…”

Section: Methodsmentioning

confidence: 99%

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Antoniak

Tatsumi²,

Schmedes³

et al. 2021

Journal of Thrombosis and Haemostasis

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“…To delete PAR1 in CFs (PAR1ΔCF), we used mice expressing Cre recombinase under the transcription factor 21 (TCF21) obtained from Dr. Tallquist 34 . Female PAR1 fl/fl mice 35 , 36 were crossed with male Cre-expressing mice to generate PAR1 fl/fl ;Mlc2v Cre and PAR1 fl/fl ;TCF21 Cre-ERT2 . To activate TCF21 Cre-ERT2 expression 34 , 37 in PAR1 fl/fl ;TCF21 Cre-ERT2 mice, 6 week old mice were gavaged with 2 mg of tamoxifen (Sigma-Aldrich, St. Louis, MO, USA) for 5 consecutive days and then mice used 5 days later.…”

Section: Methodsmentioning

confidence: 99%

Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

Bode

Schmedes

Egnatz

et al. 2021

Sci Rep

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Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.

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Cell type‐specific mechanisms coupling protease‐activated receptor‐1 to infectious colitis pathogenesis

Cited by 12 publications

References 55 publications

Activated Protein C Protects against Murine Contact Dermatitis by Suppressing Protease-Activated Receptor 2

Activated Protein C Protects against Murine Contact Dermatitis by Suppressing Protease-Activated Receptor 2

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus

Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

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