Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2–positive dendritic cells in allergic asthma

Cho, Minkyoung; Lee, Jeong Eun; Lim, Hye‐Sun; Shin, Hyun Woo; Khalmuratova, Roza; Choi, Garam; Kim, Hyuk Soon; Choi, Wahn Soo; Park, Young Jun; Shim, In‐Bo; Kim, Byung Seok; Kang, Chung Nam; Kim, Jae Ouk; Tanaka, Shinya; Kubo, Masato; Tung, H.Y. Lim; Landers, Cameron T.; Corry, David B.; Kheradmand, Farrah; Chung, Yeonseok

doi:10.1016/j.jaci.2017.09.019

Cited by 22 publications

(25 citation statements)

References 35 publications

(49 reference statements)

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“…Another mouse model study identified a potential pathway linking protease allergen exposure to airway programmed cell death ligand 2 (PD-L2) expressing T H 2-skewing dendritic cells. 63 This novel pathway was based on protease-induced fibrinogen cleavage products acting on mast cells, leading to release of IL-13, which skewed the dendritic cells to become ''T H 2-favorable PD-L2 1 '' cells. Whether this pathway is operative in human subjects remains to be determined.…”

Section: Risk Of Asthmamentioning

confidence: 99%

“…In particular, the interconnectedness between the microbiome and the risk of development of asthma (and wheeze) was a prominent feature of these studies, as was the identification of cellular stress (and in particular ORMDL3) as a mechanism for asthma development. 4,5,15,63,64 Nonetheless, all of the investigations discussed have greatly expanded our knowledge base, and the future will tell whether these findings lead to novel therapies and/or better targeting of our therapies to specific patient populations.…”

Section: Biomarker Discovery In Asthmatic Patientsmentioning

confidence: 99%

“…4,5 d Cellular stress, specifically a role for ORMDL3, might prove to be a novel therapeutic target as a mechanistic cause of airway hyperreactivity and asthma development. 15,63,64 d Newer imaging modalities to assess lung function include quantitated computed tomography, which can help estimate airway wall remodeling and air trapping. 76,77 d Recent biologics for use in asthma include upstream targets, such as anti-TSLP (tezepelumab), and downstream targets, such as anti-IgE (omalizumab), anti-IL-5 (mepolizumab and benralizumab), and anti-IL-4/IL-13 (dupilumab), which have all been shown to decrease asthma exacerbations.…”

Section: Key Advancesmentioning

confidence: 99%

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Advances in asthma in 2017: Mechanisms, biologics, and genetics

Grayson

Feldman

Prince

et al. 2018

Journal of Allergy and Clinical Immunology

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This review summarizes some of the most significant advances in asthma research over the past year. We first focus on novel discoveries in the mechanism of asthma development and exacerbation. This is followed by a discussion of potential new biomarkers, including the use of radiographic markers of disease. Several new biologics have become available to the clinician in the past year, and we summarize these advances and how they can influence the clinical delivery of asthma care. After this, important findings in the genetics of asthma and heterogeneity in phenotypes of the disease are explored, as is the role the environment plays in shaping the development and exacerbation of asthma. Finally, we conclude with a discussion of advances in health literacy and how they will affect asthma care.

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Section: Risk Of Asthmamentioning

confidence: 99%

Section: Biomarker Discovery In Asthmatic Patientsmentioning

confidence: 99%

Section: Key Advancesmentioning

confidence: 99%

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Advances in asthma in 2017: Mechanisms, biologics, and genetics

Grayson

Feldman

Prince

et al. 2018

Journal of Allergy and Clinical Immunology

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“…Fibrinogen had an Mo-DC maturation effect comparable with poly I:C, TNF-α, and PGE 2 , but it failed to induce IL-12 production ( 118 ). On the other hand, it has been recently reported that fibrinogen cleavage products generated by protease allergens, through induction of IL-13 production by mast cells, increased the number of T H 2-favorable (PD-L2 + ) DCs in allergic asthma ( 119 ). Interestingly, another member of the fibrinogen-related protein superfamily, soluble fibroleukin or fibrinogen-like protein 2 (sFGL2), highly inducible by IFN-γ and with features of APP, has a 50 kDa weight and is highly expressed in cytotoxic T cells and Tregs upon activation ( 120 ).…”

Section: Tolerogenic Actions Of Apps On Dcsmentioning

confidence: 99%

Exploring the Immunomodulatory Moonlighting Activities of Acute Phase Proteins for Tolerogenic Dendritic Cell Generation

2018

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The acute phase response is generated by an overwhelming immune-inflammatory process against infection or tissue damage, and represents the initial response of the organism in an attempt to return to homeostasis. It is mediated by acute phase proteins (APPs), an assortment of highly conserved plasma reactants of seemingly different functions that, however, share a common protective role from injury. Recent studies have suggested a crosstalk between several APPs and the mononuclear phagocyte system (MPS) in the resolution of inflammation, to restore tissue integrity and function. In fact, monocyte-derived dendritic cells (Mo-DCs), an integral component of the MPS, play a fundamental role both in the regulation of antigen-specific adaptive responses and in the development of immunologic memory and tolerance, particularly in inflammatory settings. Due to their high plasticity, Mo-DCs can be modeled in vitro toward a tolerogenic phenotype for the treatment of aberrant immune-inflammatory conditions such as autoimmune diseases and allotransplantation, with the phenotypic outcome of these cells depending on the immunomodulatory agent employed. Yet, recent immunotherapy trials have emphasized the drawbacks and challenges facing tolerogenic Mo-DC generation for clinical use, such as reduced therapeutic efficacy and limited in vivo stability of the tolerogenic activity. In this review, we will underline the potential relevance and advantages of APPs for tolerogenic DC production with respect to currently employed immunomodulatory/immunosuppressant compounds. A further understanding of the mechanisms of action underlying the moonlighting immunomodulatory activities exhibited by several APPs over DCs could lead to more efficacious, safe, and stable protocols for precision tolerogenic immunotherapy.

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“…Furthermore, thrombin, the classic activator of coagulation, can also cleave fibrinogen into FCPs resulting in further upregulation of the TLR4 pathway. A recent study identifies a programmed cell death 1 ligand 2 + (PD-L2 + ) DC phenotype which accounts for the induction of Th2 cell response upon protease allergens exposure and fibrinogen-cleavage products can promote the generation of PD-L2 + DC through TLR4 (Cho M. et al, 2017 ). These studies suggest that TLR4 plays a critical role in the allergic response upon exposure to exogenous proteases.…”

Section: Introductionmentioning

confidence: 99%

Emerging Role of Proteases in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

Wei

Bleier

2018

Front. Cell. Infect. Microbiol.

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Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous upper airway disease with multiple etiologies. Clinically, CRSwNP can be classified into either eosinophilic or non-eosinophilic subtypes. The eosinophilic phenotype of CRSwNP is widely thought to be highly associated with recurrence of nasal polyps or surgical failure. Epithelial cells have a crucial role in the development of Th2-biased airway diseases. Recent studies have shown that a wide range of external stimuli such as allergens and microorganisms can elicit the release of epithelial-derived Th2-driving cytokines and chemokines. Protease activity is a feature common to these multiple environmental insults and there is growing evidence for the concept that an imbalance of proteases and protease inhibitors in the epithelial barrier leads to both the initiation and maintenance of chronic eosinophilic airway inflammation. In this review, we analyze recent work on the role of proteases in the development of the sinonasal mucosal type 2 immune response with an emphasis on the molecular pathways promoting adaptive Th2 cell immunity.

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Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2–positive dendritic cells in allergic asthma

Abstract: Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of T2-favorable PD-L2 DCs in allergic asthma and suggest that targeting the PD-L2 DC pathway might be effective in suppressing allergic T-cell responses in the airway.

Cited by 22 publications

References 35 publications

Advances in asthma in 2017: Mechanisms, biologics, and genetics

Advances in asthma in 2017: Mechanisms, biologics, and genetics

Exploring the Immunomodulatory Moonlighting Activities of Acute Phase Proteins for Tolerogenic Dendritic Cell Generation

Emerging Role of Proteases in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

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