Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen
James D. Nolin, Ying Lai, Herbert Luke Ogden, Anne M. Manicone, Ryan C. Murphy, Dowon An, Charles W. Frevert, Farideh Ghomashchi, Gajendra S. Naika, Michael H. Gelb, Gail M. Gauvreau, Adrian M. Piliponsky, William A. Altemeier, Teal S. Hallstrand
James D. Nolin, Ying Lai, Herbert Luke Ogden, Anne M. Manicone, Ryan C. Murphy, Dowon An, Charles W. Frevert, Farideh Ghomashchi, Gajendra S. Naika, Michael H. Gelb, Gail M. Gauvreau, Adrian M. Piliponsky, William A. Altemeier, Teal S. Hallstrand
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Research Article Immunology Inflammation

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

Abstract

Phospholipase A2 (PLA2) enzymes regulate the formation of eicosanoids and lysophospholipids that contribute to allergic airway inflammation. Secreted PLA2 group X (sPLA2-X) was recently found to be increased in the airways of asthmatics and is highly expressed in airway epithelial cells and macrophages. In the current study, we show that allergen exposure increases sPLA2-X in humans and in mice, and that global deletion of Pla2g10 results in a marked reduction in airway hyperresponsiveness (AHR), eosinophil and T cell trafficking to the airways, airway occlusion, generation of type-2 cytokines by antigen-stimulated leukocytes, and antigen-specific immunoglobulins. Further, we found that Pla2g10–/– mice had reduced IL-33 levels in BALF, fewer type-2 innate lymphoid cells (ILC2s) in the lung, less IL-33–induced IL-13 expression in mast cells, and a marked reduction in both the number of newly recruited macrophages and the M2 polarization of these macrophages in the lung. These results indicate that sPLA2-X serves as a central regulator of both innate and adaptive immune response to proteolytic allergen.

Authors

James D. Nolin, Ying Lai, Herbert Luke Ogden, Anne M. Manicone, Ryan C. Murphy, Dowon An, Charles W. Frevert, Farideh Ghomashchi, Gajendra S. Naika, Michael H. Gelb, Gail M. Gauvreau, Adrian M. Piliponsky, William A. Altemeier, Teal S. Hallstrand

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Figure 2

Pla2g10–/– mice are protected from developing airway hyperresponsiveness (AHR) and aberrant lung inflammation.

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Pla2g10–/– mice are protected from developing airway hyperresponsivenes...
(A) HDM sensitization and challenge model used to induce allergic airway disease. Animals were instilled with 100 μg HDM (protein) on day 0, and then 25 μg HDM (protein) on days 7–11 and 14–18. On day 21, airway mechanics were assessed and mice were sacrificed. o.p., oropharyngeal administration. (B) Cells in the BALF following HDM sensitization and challenge were isolated and counted using an automated cell counter (n = 3/group for Sal, 7 for WT HDM, and 8 for Pla2g10–/– HDM). Mean ± SEM. (C) Single cell suspensions of lung leukocytes following HDM sensitization and challenge were isolated from digested lung tissue and counted using an automated cell counter (n = 3/group for Sal, 7 for WT HDM, and 8 for Pla2g10–/– HDM). Mean ± SEM. (D and E) Measurement of AHR to increasing doses of methacholine following HDM sensitization and challenge using the forced oscillation technique to measure lung mechanics (n = 3/group for Sal, 10 for WT HDM, and 12 for Pla2g10–/– HDM). Mean ± SEM. Statistical significance was determined by 2-way ANOVA with uncorrected Fisher’s LSD.