Breast regression protein-39 (BRP-39) promotes dendritic cell maturation in vitro and enhances Th2 inflammation in murine model of asthma

Xu, Qian; Chai, Shoujie; Qian, Yingying; Zhang, Min; Wang, Kai

doi:10.1038/aps.2012.154

Cited by 12 publications

(4 citation statements)

References 29 publications

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“…While the role of BRP-39 in fungal asthma has not been previously investigated, study of Chi3l1 À/À mice in ovalbumin (OVA) and house dust mite (HDM) models of asthma reported decreased airway resistance (improved lung function) (16). In an alternative study design where bone marrow-derived dendritic cells overexpressing BRP-39 were transferred into mice that subsequently underwent the OVA asthma model, BRP-39 was also found to drive AHR (51). OVA and HDM models of asthma primarily drive a Th2 asthma phenotype, whereas the fungal asthma model employed here attempts to recapitulate a particular endotype of human asthma (severe asthma with fungal sensitization).…”

Section: Discussionmentioning

confidence: 99%

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

Mackel

Garth

Jones

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

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Section: Discussionmentioning

confidence: 99%

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

Mackel

Garth

Jones

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…This result demonstrates their evolutionarily conserved roles as innate defense systems. Chitinase 3-like 1 (Chi3l1), also known as breast regression protein 39 (BRP-39), has been more emphasized in cancer and lung inflammation due to human homolog YKL-40, which is mainly expressed in breast cancer cells and lung macrophages 6 , 10 – 12 . In Streptococcus pneumoniae infections, Chi3l1 regulates macrophage cell death to promote bacterial clearance, indicating a function in innate immunity against pathogens 13 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis

et al. 2018

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Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we show that Chi3l1 expression was increased in activated T cells, especially in Th2 cells. In addition, Chi3l1-deficient T cells are hyper-responsive to TcR stimulation and are prone to differentiating into Th1 cells. Chi3l1-deficient Th1 cells show increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice show reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, silencing of Chi3l1 expression in the lung using peptide-siRNA complex (dNP2-siChi3l1) efficiently inhibit lung metastasis with enhanced Th1 and CTL responses. Collectively, this study demonstrates Chi3l1 is a regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity.

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“…There is a controversy with regard to the biological functions of YKL-40. In the past, YKL-40 was shown to be induced during T2 inflammation through an IL-13 dependent mechanism [51–53]. On the contrary, recent studies by Gomez and James suggested that YKL-40 and chitotriosidase were not T2-specific biomarkers in airway diseases [20, 22].…”

Section: Discussionmentioning

confidence: 99%

Chitinase-like protein YKL-40 correlates with inflammatory phenotypes, anti-asthma responsiveness and future exacerbations

et al. 2019

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Background Asthma is a heterogeneous chronic airway disease, which may be classified into different phenotypes. YKL-40 is a chitin-binding glycoprotein with unclear functions, but its expression is associated with inflammation and tissue remodeling. However, few studies have explored whether YKL-40 is associated with inflammatory phenotypes of asthma. Methods The study had two parts. Study I ( n = 115) was a one-year prospective cohort designed to explore the relationship of serum YKL-40 levels with inflammatory phenotypes of asthma at baseline, and during exacerbations. Study II ( n = 62) was a four-week prospective cohort designed to define whether serum YKL-40 levels could predict responses to a fixed anti-asthma regimen. YKL-40, IL-6 and CCL22 levels were detected using ELISA, and a sputum inflammatory panel (including IL-1β, IL-5, IL-8 and TNF-α) was assessed using Luminex-based MILLIPLEX assay. Results Study I: Serum YKL-40 levels in non-eosinophilic asthma (NEA) i.e. neutrophilic (47.77 [29.59, 74.97] ng/mL, n = 40) and paucigranulocytic (47.36 [28.81, 61.68] ng/mL, n = 31) were significantly elevated compared with eosinophilic asthma (31.05 [22.41, 51.10] ng/mL, n = 44) ( P = 0.015). Serum YKL-40levels positively correlated with blood neutrophils, sputum IL-1β and plasma IL-6 but negatively correlated with serum IgE and blood eosinophils (all P ≤ 0.05). Baseline YKL-40 levels predicted moderate to severe exacerbations within a one-year period (aOR = 4.13, 95% CI = [1.08, 15.83]). Study II: Serum YKL-40 was an independent biomarker of negative responses to anti-asthma regimens (adjusted Odds Ratio [aOR] = 0.82, 95% CI = [0.71, 0.96]. Conclusions These studies show that YKL-40 is a non-type 2 inflammatory signature for NEA, which could predict responsiveness or insensitivity to anti-asthma medications and more exacerbations. Further studies are needed to assess whether monitoring YKL-40 levels could provide potential implications for clinical relevance. Electronic supplementary material The online version of this article (10.1186/s12931-019-1051-9) contains supplementary material, which is available to authorized users.

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Breast regression protein-39 (BRP-39) promotes dendritic cell maturation in vitro and enhances Th2 inflammation in murine model of asthma

Cited by 12 publications

References 29 publications

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis

Chitinase-like protein YKL-40 correlates with inflammatory phenotypes, anti-asthma responsiveness and future exacerbations

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