Rheb1 deletion in myeloid cells aggravates OVA-induced allergic inflammation in mice

• Published in: Scientific reports Vol. 7; no. 1; p. 42655
• Main Authors: Li, Kai, Zhang, Yue, Liang, Kang Yan, Xu, Song, Zhou, Xue Juan, Tan, Kang, Lin, Jun, Bai, Xiao Chun, Yang, Cui Lan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.02.2017; Nature Publishing Group
• Subjects: 13/21; 13/31; 631/250/256/2515; 64/60; 692/699/249/2510/31; 82/1; 82/51; Asthma; Bone marrow; Bronchus; Clonal deletion; Gene deletion; Guanosine triphosphatases; Humanities and Social Sciences; Hypersensitivity; Inflammation; Leukocytes (eosinophilic); Macrophages; Mucous membrane; multidisciplinary; Myeloid cells; Ovalbumin; Polarization; Rapamycin; Ras protein; Respiratory tract; Rodents; Science; TOR protein; Tuberous sclerosis; Tuberous Sclerosis Complex 1
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep42655

The small GTPase ras homolog enriched in brain ( Rheb ) is a downstream target of tuberous sclerosis complex 1/2 ( TSC1/2 ) and an upstream activator of the mechanistic target of rapamycin complex 1 (mTORC1), the emerging essential modulator of M1/M2 balance in macrophages. However, the role and regulatory mechanisms of Rheb in macrophage polarization and allergic asthma are not known. In the present study, we utilized a mouse model with myeloid cell-specific deletion of the Rheb1 gene and an ovalbumin (OVA)-induced allergic asthma model to investigate the role of Rheb1 in allergic asthma and macrophage polarization. Increased activity of Rheb1 and mTORC1 was observed in myeloid cells of C57BL/6 mice with OVA-induced asthma. In an OVA-induced asthma model, Rheb1 -KO mice demonstrated a more serious inflammatory response, more mucus production, enhanced airway hyper-responsiveness, and greater eosinophil numbers in bronchoalveolar lavage fluid (BALF). They also showed increased numbers of bone marrow macrophages and BALF myeloid cells, elevated M2 polarization and reduced M1 polarization of macrophages. Thus, we have established that Rheb1 is critical for the polarization of macrophages and inhibition of allergic asthma. Deletion of Rheb1 enhances M2 polarization but decreases M1 polarization in alveolar macrophages, leading to the aggravation of OVA-induced allergic asthma.