title: Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1-/- mice.
abstract: Alternatively activated M2 macrophages are implicated as both regulators and agents of lung disease, but their control is poorly understood. SHIP-1 is a 5' inositol phosphatase that negatively regulates the PI3K signaling pathway implicated in inflammation. SHIP-1-deficient mice have defects in hematopoiesis and B cell development, and die prematurely due to consolidation of lungs with M2-skewed macrophages. SHIP-1 is thought to restrain M2 macrophage polarization, with deregulated M2 skewing coinciding with severe lung disease in SHIP-1-deficient mice. To determine the influence of genetic background on the lung phenotype in SHIP-1(-/-) mice, we backcrossed the SHIP-1 null mutation onto C57BL/6 (Th2-resistant) and BALB/c (Th2-prone) backgrounds. Remarkably, we found that inflammatory lung disease was severe in C57.SHIP-1(-/-) mice, but absent in BALB.SHIP-1(-/-) mice. C57.SHIP-1(-/-), but not BALB.SHIP-1(-/-) mice had greatly increased myeloid progenitors, myeloid hyperplasia, markedly enhanced numbers of activated alveolar macrophages, and elevated amounts of Th2 and proinflammatory cytokines in bronchoalveolar lavage fluid and serum, suggesting that deregulated cytokine production induced disease. C57.SHIP-1(-/-) mice also developed severe B cell-dependent autoimmune disease, which was markedly attenuated on the BALB/c background. These data demonstrate that, contrary to current concepts, loss of SHIP-1 alone is not sufficient to cause lung inflammation, with disease only manifest on a permissive genetic background. This finding questions the nature of the lung disease in SHIP-1(-/-) mice, suggesting that its M2 classification is not strictly correct. Future identification of disease-promoting loci might reveal determinants of comorbid lung disease and autoimmunity and uncover potentially useful therapeutic targets.
authors.affiliation: Ludwig Institute for Cancer Research, Victoria 3050, Australia.
authors.forename: Mhairi J
authors.initials: MJ
authors.lastname: Maxwell
authors.forename: Mubing
authors.initials: M
authors.lastname: Duan
authors.forename: Jane E
authors.initials: JE
authors.lastname: Armes
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000473:pathology; D015897:Comorbidity; D016207:Cytokines / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007249:Inflammation; D000072181:Inositol Polyphosphate 5-Phosphatases; D008171:Lung Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency*; D013045:Species Specificity
chemical_list: D016207:Cytokines; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases