Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1 -/- mice

Maxwell, Mhairi J., Duan, Mubing, Armes, Jane E., Anderson, Gary P., Tarlinton, David M. and Hibbs, Margaret L. (2011) Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1 -/- mice. Journal of Immunology, 186 12: 7164-7175. doi:10.4049/jimmunol.1004185


Author Maxwell, Mhairi J.
Duan, Mubing
Armes, Jane E.
Anderson, Gary P.
Tarlinton, David M.
Hibbs, Margaret L.
Title Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1 -/- mice
Formatted title
Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1 -/- mice
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2011-06-01
Year available 2011
Sub-type Article (original research)
DOI 10.4049/jimmunol.1004185
Open Access Status DOI
Volume 186
Issue 12
Start page 7164
End page 7175
Total pages 12
Place of publication Bethesda, United States
Publisher American Association of Immunologists
Language eng
Subject 2403 Immunology
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.
Formatted 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.
Keyword Immunology
Immunology
IMMUNOLOGY
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
 
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