Cyclooxygenase Inhibition during Allergic Sensitization Increases STAT6-Independent Primary and Memory Th2 Responses

Toki

Am J Respir Crit Care Med

et al. 2016

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115

129

Rationale: Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines central to the asthma phenotype; however, the effect of prostaglandin (PG) I 2 on ILC2 function is unknown.Objectives: To determine the effect of PGI 2 on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI 2 and the PGI 2 analog cicaprost on lung ILC2s in vivo.Methods: Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI 2 receptor-deficient (IP 2/2 ) mice were cultured with IL-33 and treated with the PGI 2 analog cicaprost. WT and IP 2/2 mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI 2 analog cicaprost. Measurement and Main Results:We demonstrate that PGI 2 inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI 2 receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI 2 signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5-and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI 2 analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5-and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI 2 analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33.Conclusions: These results suggest that PGI 2 may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.

mentioning

confidence: 99%

Prostaglandin I₂Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

Toki

Am J Respir Crit Care Med

et al. 2016

Self Cite

115

129

“…13 Therefore, Treg cells may be a mechanism by which immune tolerance prevents the immune system from responding to innocuous environmental antigens. While we and others have reported that COX inhibition increased allergic airway inflammatory responses, 6–10 the effect of COX products and COX inhibition on allergen-induced immune tolerance in the airways is not known.…”

Section: Introductionmentioning

confidence: 85%

“…4 In addition, there was a higher prevalence of new-onset asthma in subjects who regularly used NSAIDs other than aspirin compared to nonusers. 5 In animal studies, COX inhibition with indomethacin increased allergic sensitization, allergen-specific immune memory response, and augmented allergic airway inflammation and Th2 immune responses, 6–10 supporting a role for the COX pathway in the development of allergic diseases. Similarly, mice deficient in COX enzymes have increased allergic inflammation compared to wild type (WT) mice.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling

Goleniewska

Journal of Allergy and Clinical Immunology

et al. 2014

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Background The prevalence of allergic diseases doubled in developed countries in the last several decades. Cyclooxygenase (COX) inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known. Objective To determine the role of the COX pathway and PGI2 signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance. Methods Wild type (WT) BALB/c mice and IP KO mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and Th2 cytokine measurements. Results WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP KO mice had augmented inflammation and Th2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti-tolerance effect of COX inhibition. Conclusion COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and clinical use of COX inhibiting drugs may increase the risk of developing allergic diseases.

“…STAT6 is activated by both IL-4 and IL-13 and plays an important role in Th2 cell differentiation and type 2 immune responses (1). We have previously shown that the cyclooxygenase (COX) inhibitor indomethacin augmented allergic Th2 cytokine responses and lung inflammation in a STAT6-independent manner (2, 3). However, which COX product(s) suppressed by COX inhibition is critical for indomethacin-induced STAT6-independent pro-allergic effect has not been identified.…”

Section: Introductionmentioning

confidence: 99%

“…The COX pathway of arachidonic acid metabolism is responsible for the formation of PGD 2 , PGE 2 , PGF 2α , PGI 2 and thromboxane A 2 (TXA 2 ), and has immune regulatory functions in the development and manifestation of allergic diseases (2-11). COX-inhibiting drugs such as indomethacin and the COX-2 selective inhibitor NS-398 increased allergic inflammation in the airway and skin in mice (9, 12), suggesting that some lipid products formed in the COX pathway have inhibitory effects on allergic diseases.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation

The Journal of Immunology

Goleniewska

et al. 2016

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Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration–approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.