Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1(-/-) Mice

Maxwell, MJ; Duan, MB; Armes, JE; Anderson, GP; Tarlinton, DM; Hibbs, ML

Author(s): Maxwell, MJ; Duan, MB; Armes, JE; Anderson, GP; Tarlinton, DM; Hibbs, ML;
Details: Publication Year 2011-06-15,Volume 186,Issue #12,Page 7164-7175
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
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 (Th2prone) 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. SHIP1 2/2 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. The Journal of Immunology, 2011, 186: 7164-7175.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: LYN-DEFICIENT MICE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INOSITOL PHOSPHATASE SHIP; FC-GAMMA-RIIB; MACROPHAGE ACTIVATION; ALLERGIC INFLAMMATION; NEGATIVE REGULATOR; CELL DEVELOPMENT; IMMUNE-SYSTEM; MARGINAL ZONE
Publisher's Version: https://doi.org/10.4049/jimmunol.1004185
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-06-15 12:00:00