Activated protein C modulates the proinflammatory activity of dendritic cells

Μatsumoto, Takahiro; Matsushima, Yuki; Toda, Masaaki; Roeen, Ziaurahman; D’Alessandro-Gabazza, Corina N.; Hinneh, Josephine A; Harada, Eijiro; Yasuma, Taro; Yano, Yutaka; Urawa, Masahito; Kobayashi, Tetsu; Taguchi, Osamu; Gabazza, Esteban C.

doi:10.2147/jaa.s75261

Cited by 7 publications

(5 citation statements)

References 19 publications

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“…APC is a natural anticoagulant with strong anti-inflammatory and barrier protective functions, and has proven effective in limiting disease progression in various inflammatory diseases or animal models of these conditions [ 8 ]. In allergic conditions, APC suppresses antigen-induced histamine release from rat peritoneal MCs [ 53 ], decreases Th1 and Th2 cytokines, IgE and hyperresponsiveness in a mouse model of asthma [ 9 , 54 ], and reduces neutrophil influx and degranulation in allergic asthma patients [ 10 ]. Similarly, in CHS, APC exerted its anti-inflammatory function via suppressing MC infiltration and degranulation, inhibiting Th1/Th2/Th22 cells and their associated cytokines.…”

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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“… 46 However, inhalation of APC before ovalbumin-challenge in mice resulted in a strong attenuation of allergic inflammation with decreased eosinophil influx, IL-4, IL-5, and IL-13 and IgE levels in BAL fluid, and diminished AHR. 47 These findings suggest that APC plays an anti-inflammatory role through modulation of dendritic cell and neutrophil trafficking in asthma, 46 , 48 and these effects are independent of the functions of APC in the coagulation pathway. Therefore, reduced levels of APC in Type 2-high asthma reflect increased inflammation in the airway, and administration of APC inhibits inflammatory cell migration, suggesting a role as an anti-inflammatory therapeutic agent for asthma.…”

Section: Coagulation Imbalance In Type-2 High Asthmamentioning

confidence: 97%

Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity

Womble

Mcquade

Ihrie

et al. 2021

JAA

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Asthma is a common, chronic airway inflammatory disease marked by airway hyperresponsiveness, inflammation, and remodeling. Asthma incidence has increased rapidly in the past few decades and recent multicenter analyses have revealed several unique asthma endotypes. Of these, type-2 high asthma with comorbid obesity presents a unique clinical challenge marked by increased resistance to standard therapies and exacerbated disease development. The extrinsic coagulation pathway plays a significant role in both type-2 high asthma and obesity. The type-2 high asthma airway is marked by increased procoagulant potential, which is readily activated following damage to airway tissue. In this review, we summarize the current understanding of the role the extrinsic coagulation pathway plays in the airway of type-2 high asthma with comorbid obesity. We propose that asthma control is worsened in obesity as a result of a systemic and local airway shift towards a procoagulant and anti-fibrinolytic environment. Lastly, we hypothesize bariatric surgery as a treatment for improved asthma management in type-2 high asthma with comorbid obesity, facilitated by normalization of systemic procoagulant and pro-inflammatory mediators. A better understanding of attenuated coagulation parameters in the airway following bariatric surgery will advance our knowledge of biomolecular pathways driving asthma pathobiology in patients with obesity.

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“…APC signaling has emerged as a potent orchestrator of the adaptive immune response. Indirectly, APC modulates professional antigen presenting cell responses, skewing them toward a more tolerogenic phenotype and dampening their ability to prime and activate adaptive immune cells, such as CD4 + T helper (Th) cells and CD8 + cytotoxic T cells [55]. This is supported by studies in which adoptively transferred APC-treated dendritic cells were less effective in priming CD4 + T cells, resulting in significantly dampened proinflammatory Th1 and Th2 responses [55].…”

Section: The Protein C Pathway In Adaptive Immunitymentioning

confidence: 99%

“…Indirectly, APC modulates professional antigen presenting cell responses, skewing them toward a more tolerogenic phenotype and dampening their ability to prime and activate adaptive immune cells, such as CD4 + T helper (Th) cells and CD8 + cytotoxic T cells [55]. This is supported by studies in which adoptively transferred APC-treated dendritic cells were less effective in priming CD4 + T cells, resulting in significantly dampened proinflammatory Th1 and Th2 responses [55]. Mechanistically, APC inhibits the expansion and maturation of conventional proinflammatory dendritic cells and instead promotes the generation of tolerogenic plasmacytoid dendritic cells.…”

Section: The Protein C Pathway In Adaptive Immunitymentioning

confidence: 99%

“…Mechanistically, APC inhibits the expansion and maturation of conventional proinflammatory dendritic cells and instead promotes the generation of tolerogenic plasmacytoid dendritic cells. This leads to significant decrease in proinflammatory cytokine release (TNFα, IL-12p70, IL-4, IL-6) and increased formation of anti-inflammatory IL-10 [55]. This shift in the cytokine axis instructs nearby T cells to adopt an anti-inflammatory regulatory T cell (Treg) phenotype, instead of differentiating into proinflammatory effector T-cell lineages.…”

Section: The Protein C Pathway In Adaptive Immunitymentioning

confidence: 99%

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The protein C pathways

Leon

Rehill

Preston

2022

Current Opinion in Hematology

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Purpose of reviewTo provide an overview of the state-of-the-art in protein C (PC) pathway research. Recent findingsThe PC pathway is crucial for maintaining hemostasis to prevent venous thromboembolism. This is evident from genetic mutations that result in impaired PC pathway activity and contribute to increased venous thromboembolism risk in affected individuals. In addition to its anticoagulant role, activated PC (APC) also mediates a complex, pleiotropic role in the maintenance of vascular cell health, which it achieves via antiinflammatory and antiapoptotic cell signaling on endothelial cells. Emerging data have demonstrated that cell signaling by APC, mediated by multiple receptor interactions on different cell types, also confers cytoprotective and anti-inflammatory benefits. Defects in both arms of the PC pathway are associated with increased susceptibility to thrombo-inflammatory disease in various preclinical thrombotic, proinflammatory and neurological disease models. Moreover, recent studies have identified attenuation of anticoagulant PC pathway activity as an exciting therapeutic opportunity to promote hemostasis in patients with inherited or acquired bleeding disorders.

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Activated protein C modulates the proinflammatory activity of dendritic cells

Cited by 7 publications

References 19 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

Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity

The protein C pathways

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