SHIP deficiency causes Crohn's disease-like ileitis

Kerr, William G; Park, Mi-Young; Maubert, Monique; Engelman, Robert W

CD pathology begins with the formation of multiple aphthoid ulcers infiltrated by neutrophils, which progress and coalesce into sharply delimited, regional, transmural inflammations with formation of strictures, fissures and fistulas. 1e4 Here we show that mutation of the SHIP1 locus leads to a comparable ileitis dominated by neutrophils. Although elements of CD pathology are lacking in the SHIP-deficient mouse described herein, including development of multiple aphthoid ulcers, pyloric gland metaplasia, granulation tissue, and fistula formation, many CD histopathological features are present. SHIP-deficient ileitis is not precipitated by an apparent dysfunction on the part of SHIPdeficient parenchymal elements as reconstitution of SHIP À/À hosts with SHIP-competent haematolymphoid cells prevents development of ileitis. However, these same hosts still retain some facets of eosinophilic crystalline pneumonia indicating that SHIP À/À parenchymal elements may contribute to the lung pathology found in germline SHIP-deficient mice. Conversely, we find that transfer of SHIP-deficient haematolymphoid cells from the spleen is sufficient to trigger CD-like ileitis in an immunocompetent host. Transfer of cells capable of a cellmediated immune attack, T cells and NK cells, do not elicit this CD-like ileitis. These findings suggest that a SHIP-deficient myeloid cell may promote the CD-like enteritis that occurs in SHIP-deficient mice. Granulocytes are less susceptible to apoptotic signals in SHIP-deficient mice, granulocyteemonocyte infiltrations can be found in various tissues of SHIP-deficient mice, 44 and mononuclear phagocytes are essential for maintenance of intestinal homeostasis. 50 Retention of components of eosinophilic crystalline pneumonia in the SHIP À/À hosts reconstituted with WT BM indicates that aspects of this lung pathology are of a parenchymal, cell autonomous origin. Mass spectrometry analyses have identified Ym1 as the principal crystalline protein of this pneumonia, perhaps secreted by activated alveolar macrophages, and proposed to be involved in eosinophil recruitment, immune activation and tissue repair. 34 However, since SHIP-deficient mice that undergo allogeneic BM transplant have a normal lifespan, 32 these retained features of pulmonary pathology are apparently not sufficient to progress to the fatal lung consolidation that occurs in germline, SHIP-deficient mice. 41 Further, with the present observations, CD-like enteritis should be included among the pathologies that develop and contribute to morbidity and mortality in germline, SHIP-deficient mice.