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Extracellular Matrix Protein Mindin is Required for the Complete Allergic Response to Fungal-Associated Proteinase.

ABSTRACT: Asthma remains an important cause of morbidity and mortality with an incidence that continues to rise. Despite the importance of this disease, the mechanisms by which the host develops allergic airways disease remain poorly understood. The development of allergic airways disease appears to be contingent on activation of both the innate and adaptive immune system, but little is known about the cross-talk between these two systems. The extracellular matrix protein mindin (Spondin 2) has been previously demonstrated to have functional roles in both the innate and adaptive immunological responses. Previous work supports that pulmonary challenge with fungal-associated allergenic proteinase (FAP) induces an innate allergic response. We hypothesized that mindin would modify the biological response to FAP. Saline or FAP was administered by oropharyngeal aspiration to C57BL/6 wild type or mindin-null mice every 4 days for a total of five exposures. FAP exposed C57BL/6 mice developed enhanced airway hyperresponsiveness (AHR) to methacholine challenge and increased neutrophils and eosinophils in the bronchoalveolar lavage as compared to saline exposed controls. These responses were significantly reduced in mindin-null mice exposed to FAP. FAP challenge was associated with a broad induction of cytokines (IL-1?, TNF?, Th1, Th2, and IL-17), chemokines, and growth factors, which were reduced in mindin-null mice exposed to FAP. RNA expression in lung monocytes for representative M1 and M2 activation markers were increased by FAP, but were independent of mindin. Our observations support that challenge with FAP results in activation of both innate and adaptive immune signaling pathways in a manner partially dependent on mindin. These findings suggest a potential role for the extracellular matrix protein mindin in cross-talk between the innate and adaptive immune systems.

SUBMITTER: Tighe RM

PROVIDER: S-EPMC3613851 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Extracellular Matrix Protein Mindin is Required for the Complete Allergic Response to Fungal-Associated Proteinase.

Tighe Robert M RM Potts Erin N EN Feng Feifei F Li Zhuowei Z Frush Benjamin B He You-Wen YW Corry David B DB Noble Paul W PW Hollingsworth John W JW

Journal of allergy & therapy 20110901 Suppl 1

Asthma remains an important cause of morbidity and mortality with an incidence that continues to rise. Despite the importance of this disease, the mechanisms by which the host develops allergic airways disease remain poorly understood. The development of allergic airways disease appears to be contingent on activation of both the innate and adaptive immune system, but little is known about the cross-talk between these two systems. The extracellular matrix protein mindin (Spondin 2) has been previ ...[more]

PMID: 23560245

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Project description:BackgroundOur previous work demonstrated that the extracellular matrix protein mindin contributes to allergic airways disease. However, the role of mindin in nonallergic airways disease has not previously been explored.ObjectivesWe hypothesized that mindin would contribute to airways disease after inhalation of either lipopolysaccharide (LPS) or ozone.MethodsWe exposed C57BL/6J and mindin-deficient (-/-) mice to aerosolized LPS (0.9 ?g/m3 for 2.5 hr), saline, ozone (1 ppm for 3 hr), or filtered air (FA). All mice were evaluated 4 hr after LPS/saline exposure or 24 hr after ozone/FA exposure. We characterized the physiological and biological responses by analysis of airway hyperresponsiveness (AHR) with a computer-controlled small-animal ventilator (FlexiVent), inflammatory cellular recruitment, total protein in bronchoalveolar lavage fluid (BALF), proinflammatory cytokine profiling, and ex vivo bronchial ring studies.ResultsAfter inhalation of LPS, mindin-/- mice demonstrated significantly reduced total cell and neutrophil recruitment into the airspace compared with their wild-type counterparts. Mindin-/- mice also exhibited reduced proinflammatory cytokine production and lower AHR to methacholine challenge by FlexiVent. After inhalation of ozone, mice had no detectible differences in cellular inflammation or total BALF protein dependent on mindin. However, mindin-/- mice were protected from increased proinflammatory cytokine production and AHR compared with their C57BL/6J counterparts. After ozone exposure, bronchial rings derived from mindin-/- mice demonstrated reduced constriction in response to carbachol.ConclusionsThese data demonstrate that the extracellular matrix protein mindin modifies the airway response to both LPS and ozone. Our data support a conserved role of mindin in production of proinflammatory cytokines and the development of AHR in two divergent models of reactive airways disease, as well as a role of mindin in airway smooth muscle contractility after exposure to ozone.

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Extracellular Matrix Protein Mindin is Required for the Complete Allergic Response to Fungal-Associated Proteinase.

Publications

Extracellular Matrix Protein Mindin is Required for the Complete Allergic Response to Fungal-Associated Proteinase.

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