Secretory Leukocyte Protease Inhibitor Plays an Important Role in the Regulation of Allergic Asthma in Mice

Marino, Rafael; Thuraisingam, Thusanth; Camateros, Pierre; Kanagaratham, Cynthia; Xu, Yong; Henri, Jennifer; Yang, Jingxuan; He, Guoan; Ding, Aihao; Radzioch, Danuta

doi:10.4049/jimmunol.1001539

Cited by 40 publications

(31 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, SLPI promotes cutaneous wound healing, cell proliferation of epithelial cells, prevents HIV infection, exhibits antimicrobial and antifungal functions, inhibits NF-kB activation, and modulates macrophage functions (6,37). The protective effect of SLPI as an anti-inflammatory mediator has been documented in inflammatory lung diseases, including chronic obstructive pulmonary disease, cystic fibrosis (38), and allergic asthma (37).…”

Section: Discussionmentioning

confidence: 99%

“…SLPI is a serine proteinase inhibitor constitutively expressed in mucosal tissues and immune cells, including monocytes, macrophages, and neutrophils (35,36) that exerts pleiotropic activities in different biological systems (7). For example, SLPI promotes cutaneous wound healing, cell proliferation of epithelial cells, prevents HIV infection, exhibits antimicrobial and antifungal functions, inhibits NF-kB activation, and modulates macrophage functions (6,37). The protective effect of SLPI as an anti-inflammatory mediator has been documented in inflammatory lung diseases, including chronic obstructive pulmonary disease, cystic fibrosis (38), and allergic asthma (37).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Vago

Tavares

Sugimoto

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties. Intact AnxA1 is a 37-kDa protein that may be cleaved in vivo at the N-terminal region by neutrophil proteases including elastase and proteinase-3, generating the 33-kDa isoform that is largely inactive. In this study, we investigated the dynamics of AnxA1 expression and the effects of synthetic (sivelestat [SIV]; Eglin) and natural (secretory leukocyte protease inhibitor [SLPI]; Elafin) protease inhibitors on the resolution of LPS-induced inflammation. During the settings of LPS inflammation AnxA1 cleavage associated closely with the peak of neutrophil and elastase expression and activity. SLPI expression increased during resolving phase of the pleurisy. Therapeutic treatment of LPS-challenge mice with recombinant human SLPI or Elafin accelerated resolution, an effect associated with increased numbers of apoptotic neutrophils in the pleural exudates, inhibition of elastase, and modulation of the survival-controlling proteins NF-κB and Mcl-1. Similar effects were observed with SIV, which dose-dependently inhibited neutrophil elastase and shortened resolution intervals. Mechanistically, SIV-induced resolution was caspase-dependent, associated to increased levels of intact AnxA1 and decreased expression of NF-κB and Mcl-1. The proresolving effect of antiproteases was also observed in a model of monosodium urate crystals–induced inflammation. SIV skewed macrophages toward resolving phenotypes and enhanced efferocytosis of apoptotic neutrophils. A neutralizing antiserum against AnxA1 and a nonselective antagonist of AnxA1 receptor abolished the accelerated resolution promoted by SIV. Collectively, these results show that elastase inhibition not only inhibits inflammation but actually promotes resolution, and this response is mediated by protection of endogenous intact AnxA1 with ensuing augmentation of neutrophil apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Vago

Tavares

Sugimoto

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…SLPI is expressed by the airway epithelium and was previously associated with suppression of asthma features in mouse models (24,25). Indeed, Ifng -/-mice with greater SLPI expression were resistant to development of AHR ( Figure 6A).…”

Section: Introductionmentioning

confidence: 99%

High IFN-γ and low SLPI mark severe asthma in mice and humans

Raundhal¹,

Morse²,

Khare³

et al. 2015

J. Clin. Invest.

334

304

View full text Add to dashboard Cite

Results SA subjects harbor more IFN-γ + CD4+ T cells in their airways compared with MMA subjects. A total of 66 subjects, 33 classified with MMA and 33 classified with SA, were included in this study; details of patient characteristics are included in Table 1. Of note, biological samples, such as cells in BAL fluid used for differential cell counts and cytokine expression, were analyzed from a subset of these subjects based on availability, as described in each figure legend. Since the recovery of BAL Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng -/-mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra -/-mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

show abstract

“…One further caveat regarding therapeutic targeting of TSLP is that TSLP can contribute to epithelial repair both by inducing the secretory leukocyte protease inhibitor (SLPI) and via other mechanisms (Reardon et al, 2011;Semlali et al, 2010). Expression of SLPI has the potential to dampen allergic airway inflammation, and interfering with TSLP therapeutically might abolish this protective pathway (Marino et al, 2011).…”

Section: Gm-csf and Tslpmentioning

confidence: 99%

Epithelial Cell Regulation of Immune Responses in the Lung

Hammad

2015

Mucosal Immunology

View full text Add to dashboard Cite

Secretory Leukocyte Protease Inhibitor Plays an Important Role in the Regulation of Allergic Asthma in Mice

Cited by 40 publications

References 48 publications

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

High IFN-γ and low SLPI mark severe asthma in mice and humans

Epithelial Cell Regulation of Immune Responses in the Lung

Contact Info

Product

Resources

About