Ablation of Mina53 in Mice Reduces Allergic Response in the Airways

Abstract

ABSTRACT. The mina53 (myc-induced nuclear antigen with a 53 kDa molecular mass; also known as mina) was identified as a direct transcriptional target of the oncoprotein Myc and encodes a conserved protein in vertebrates. While Mina53 is known to be associated with tumorigenesis, it is not clear what role Mina53 plays in non-neoplastic tissues. To directly address the roles of Mina53 in non-neoplastic tissues, we created mina53-deficient mice. Both male and female mina53-deficient mice reached adulthood and were fertile, suggesting that Mina53 is dispensable for the basic developmental processes. Since we found that Mina53 was expressed in cells responsible for immune responses, we investigated whether Mina53 was involved in immune responses. When mice were exposed intranasally to house dust mites as an allergen, the airway tract showed hyperresponsiveness to methacholine in wild-type mice but not in mina53-deficient mice. The mina53-deficient mice also showed a significantly reduced migration of immune cells, including eosinophils, into bronchoalveolar lavage fluid compared with wild-type mice. The levels of Th2 cytokines, IL-4 and IL-5, produced in response to house dust mites were lower in the mina53-deficient mice than in wild-type mice. The level of IFN-γ in bronchoalveolar lavage fluid was significantly decreased by exposure to house dust mites in wild-type mice but not in the mina53-deficient mice. These results suggest that Mina53 plays a role in the allergic response to inhaled allergens, possibly through controlling IL-4 production.

A SNP uncoupling Mina expression from the TGFβ signaling pathway

“…Consistent with this, Mina KO mice exhibited protection from silica‐induced lung fibrosis, associated with impaired Th17 and elevated iTreg cell infiltration in the lung 7. Further, in a house dust mite model of allergic asthma, Mina KO mice exhibited attenuated airway disease 6. And finally, genetic variation at the MINA locus was found in a Han Chinese population to be associated with the development of childhood atopic asthma 15.…”

“…We recently found that Mina KO mice harboring a deletion spanning exons 3 and 4 (encoding the catalytic JmjC domain) were developmentally normal and fertile but exhibited a defect in Th17 development 3 and expelled parasitic nematodes more efficiently than their WT counterparts (due to an intestinal epithelial cell‐intrinsic defect) (manuscript submitted). An independently‐derived Mina KO mouse strain in which exon 2 was replaced with a Neo cassette was also viable and fertile; furthermore, in an experimental model of house dust mite allergic airway inflammation it exhibited disease resistance that the authors suggested may arise from an observed defect in IL4 regulation 6. However, it is possible that ameliorated airway disease in the exon2/Neo replacement strain resulted instead from a defective Th17 response (not explored in their report).…”

“…Mina is a widely but non‐uniformly expressed gene with pleiotropic functions 1, 2, 3, 4, 5, 6, 7. It is likely that the four validated CREs (E1–E4) as well as the additional three likely to reside near DHSs 1, 7, and 8 coordinate to confer tissue‐, developmental stage‐, and signaling‐specificity upon Mina transcription.…”

“…Mina is a widely expressed pleiotropic protein with known oncogenic and immunoregulatory roles 1, 2, 3, 4, 5, 6, 7. Originally discovered as a Myc‐induced nuclear antigen of 53 kDa with pro‐proliferative activity in promyelocytic leukemia HL60 cells 1, it has subsequently been shown to be overexpressed in a wide variety of human cancers, in some cases providing prognostic value 2.…”

From biological mechanisms to clinical implications: the role of mineral dust-induced gene in lung cancers

“…Mori et al (17) reported that Mdig/mina53 has a great impact on allergic asthmatic response by regulating the allergic response via IL-4 production in an allergic asthma model. They found airway hyperresponsiveness to methacholine in wild-type mice but not in Mdig/mina53-deficient mice after challenging with house dust mite allergens.…”