Chitin Elicits CCL2 from Airway Epithelial Cells and Induces CCR2-Dependent Innate Allergic Inflammation in the Lung

Mesenchymal stem cell (MSC) transplantation alleviates metabolic defects in diseased recipient cells by intercellular mitochondrial transport (IMT). However, the effect of host metabolic conditions on MSCs in general, and IMT in particular, has largely remained unexplored. This study has identified a molecular pathway that primarily governs the metabolic function and IMT of MSCs. We found underlying mitochondrial dysfunction, impaired mitophagy, and reduced IMT in MSCs derived from high-fat diet (HFD)-induced obese mice (MSC-Ob). Mechanistically, MSC-Ob failed to sequester their damaged mitochondria into LC3-dependent autophagosomes due to decrease in mitochondrial cardiolipin content, which we propose as a putative mitophagy receptor for LC3 in MSCs. Functionally, MSC-Ob exhibited diminished potential to rescue metabolic deficits and cell death in stress-induced epithelial cells. In a small molecule screen, we found pyrroloquinoline quinone (PQQ) as a regulator of mitophagy and IMT. Long-term culture of MSC-Ob with PQQ (MSC-ObPQQ) restored cardiolipin content and sequestration of mitochondria to autophagosomes with concomitant activation of mitophagy. Upon co-culture, MSC-ObPQQ rescued cell death in stress-induced epithelial cells by enhancing IMT. The beneficial effect of PQQ was also evident in MSCs derived from human subjects in an in vitro model. In two independent mice models, the transplantation of MSC-ObPQQ restored IMT to airway epithelial cells, improved their mitochondrial metabolism and attenuated features of allergic airway inflammation (AAI). However, unmodulated MSC-Ob failed to do so. In summary, we uncover the molecular mechanism leading to the therapeutic decline of obese-derived MSCs and highlight the importance of pharmacological modulation of these cells for therapeutic intervention.

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Airway Epithelial Cells in Various Models of Bronchial Allergic Inflammation in Guinea Pigs

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463209200500302 ◽

1992 ◽

Vol 5 (3) ◽

pp. 165-172

Author(s):

J.P. Tarayre ◽

M. Aliaga ◽

M. Barbara ◽

N. Malfetes ◽

S. Vieu

Keyword(s):

Epithelial Cells ◽

Anaphylactic Reaction ◽

Guinea Pigs ◽

Allergic Inflammation ◽

Lavage Fluid ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Freund’S Complete Adjuvant ◽

Freund's Complete Adjuvant ◽

Similar Intensity

The number of airway epithelial cells (AEC) in bronchus lumen after various types of anaphylactic shock of similar intensity was determined in guinea pigs. Aerosol-induced anaphylactic shocks were studied after four types of active sensitization: sensitization by IM injection of 30 mg/kg ovalbumin mixed with Freund's complete adjuvant; sensitization by IM injection of 30 mg/kg ovalbumin; sensitization by IP injection of 1 μg ovalbumin and 50 mg A1 (OH)3 by animal; sensitization by 2 exposures to 1%-ovalbumin aerosol at a 7-day interval. One, 3,6,24 and 48 h after the anaphylactic reaction the number of AEC in bronchoalveolar lavage fluid (BALF) was counted in comparison to guinea pigs sensitized but exposed to 0.9% NaCl aerosol. The number of AEC was significantly increased only 24–48 h after the shock in animals sensitized with ovalbumin in Freund's complete adjuvant. In animals passively sensitized by antiserum obtained with sensitization by ovalbumin in Freund's complete adjuvant and challenged by IV or aerosol administration of antigen, non rise in the number of AEC was obtained 24–48 h after the shock. The higher amount of AEC 24–48 h after the anaphylactic reaction in animals actively sensitized by ovalbumin in Freund's complete adjuvant could be related to the higher increase in the number of neutrophils and of mononuclears obtained in the BALF at these times in comparison to other types of active sensitization. The rise in the number of AEC only after the active reaction seems to show the part played by T-lymphocytes in the induction of this effect. The increase in the number of eosinophils in BALF and the appearance of the hyperreactivity cannot be related to the rise in the AEC in bronchus lumen.

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Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00364.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. L502-L511 ◽

Cited By ~ 59

Author(s):

Robert J. Homer ◽

Zhou Zhu ◽

Lauren Cohn ◽

Chun Gun Lee ◽

Wendy I. White ◽

...

Keyword(s):

Epithelial Cells ◽

Allergic Inflammation ◽

Secretory Protein ◽

Airway Epithelial Cells ◽

Clara Cell ◽

Parasitic Nematodes ◽

Secretory Cells ◽

Airway Epithelial ◽

Fungal Cell ◽

Clara Cell Secretory Protein

The mammalian chitinase family includes members both with and without enzymatic activity against chitin, a product of fungal cell walls, exoskeletons of crustaceans and insects, and the microfilarial sheaths of parasitic nematodes. Two members of that family, Ym1 and acidic mammalian chitinase (AMCase), are strongly upregulated in pulmonary T helper (Th) 2 inflammation but not in Th1 inflammation. The sites of expression of these products are incompletely known. We show here that, in two different models of Th2 inflammation, Ym1 and AMCase are mutually exclusively expressed in proximal vs. distal airway epithelium, respectively, whereas both are expressed in alveolar macrophages. This regional difference along the airway corresponds to the previously noted distinction between mucus positive proximal cells and mucus negative distal cells under the same conditions. Among distal cells, AMCase colocalizes with epithelial cells expressing the Clara cell marker Clara cell secretory protein. These AMCase-expressing cells retain expression of FOXA2, a transcription factor whose downregulation in association with IL-13 signaling has previously been associated with production of mucus in proximal airway epithelial cells. These results provide evidence that secretory cells of proximal and distal airways undergo fundamentally different gene expression programs in response to allergic inflammation. Furthermore, AMCase provides the first positive molecular marker of distal Clara cell secretory protein-expressing cells under these conditions.

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Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells

Biochemical Journal ◽

10.1042/bj20120057 ◽

2012 ◽

Vol 446 (3) ◽

pp. 383-394 ◽

Cited By ~ 21

Author(s):

Kyubo Kim ◽

Youlia M. Petrova ◽

Brenton L. Scott ◽

Rupesh Nigam ◽

Anurag Agrawal ◽

...

Keyword(s):

Epithelial Cells ◽

Essential Gene ◽

Allergic Inflammation ◽

Airway Epithelial Cells ◽

Secretory Cells ◽

Airway Epithelial ◽

Response Element ◽

Protein Levels ◽

Mucous Metaplasia ◽

Specificity Protein

Airway mucin secretion and MC (mast cell) degranulation must be tightly controlled for homoeostasis of the lungs and immune system respectively. We found the exocytic protein Munc18b to be highly expressed in mouse airway epithelial cells and MCs, and localized to the apical pole of airway secretory cells. To address its functions, we created a mouse with a severely hypomorphic Munc18b allele such that protein expression in heterozygotes was reduced by ~50%. Homozygous mutant mice were not viable, but heterozygotes showed a ~50% reduction in stimulated release of mucin from epithelial cells and granule contents from MCs. The defect in MCs affected only regulated secretion and not constitutive or transporter-mediated secretion. The severity of passive cutaneous anaphylaxis was also reduced by ~50%, showing that reduction of Munc18b expression results in an attenuation of physiological responses dependent on MC degranulation. The Munc18b promoter is controlled by INR (initiator), Sp1 (specificity protein 1), Ets, CRE (cAMP-response element), GRE (glucocorticoid-response element), GATA and E-box elements in airway epithelial cells; however, protein levels did not change during mucous metaplasia induced by allergic inflammation. Taken together, the results of the present study identify Munc18b as an essential gene that is a limiting component of the exocytic machinery of epithelial cells and MCs.

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