Voglmaier, Nicole S.

mφ are heterogeneous in their functions, and although it is clear that inflammatory mφ contribute to inflammation in IBDs, multiple lines of evidence suggest that M2a mφ may offer protection during intestinal inflammation. In vivo SHIP‐deficient mouse mφ are M2a so SHIP‐deficient mice provide a unique genetic model of M2a mφ. Based on this, this study tested the hypothesis that SHIP‐deficient, M2a mφ protect mice from intestinal inflammation. The objectives were to compare the susceptibility of SHIP+/+ and SHIP−/− littermates with DSS‐induced intestinal inflammation and to determine whether protection was mφ‐mediated and whether protection could be transferred to a susceptible host. We have found that SHIP−/− mice are protected during DSS‐induced intestinal inflammation. SHIP−/− mice have delayed rectal bleeding and reduced weight loss, disruption of intestinal architecture, and immune cell infiltration during DSS‐induced colitis relative to their WT littermates. Using liposome depletion of mφ, we found that SHIP−/− mouse protection was indeed mφ‐mediated. Finally, we determined that SHIP−/− mφ‐mediated protection could be conferred to susceptible WT mice by adoptive transfer of M2a mφ derived ex vivo. This study supports our hypothesis by demonstrating that SHIP‐deficient, M2a mφ are protective in this murine model of acute intestinal inflammation. Adoptive transfer of M2a mφ to patients with IBDs offers a promising, new strategy for treatment that may be particularly useful in patients who are otherwise refractory to conventional therapies.

Intestinal fibrosis is a serious complication of Crohn's disease (CD) that can lead to stricture formation, which requires surgery. Mechanisms underlying intestinal fibrosis remain elusive because of a lack of suitable mouse models. Herein, we describe a spontaneous mouse model of intestinal inflammation with fibrosis and the profibrotic role of arginase I. The Src homology 2 domain–containing inositol polyphosphate 5′-phosphatase–deficient (SHIP –/–) mice developed spontaneous discontinuous intestinal inflammation restricted to the distal ileum starting at the age of 4 weeks. Mice developed several key features resembling CD, including inflammation and fibrosis. Inflammation was characterized by abundant infiltrating Gr-1–positive immune cells, granuloma-like immune cell aggregates that contained multinucleated giant cells, and a mixed type 2 and type 17 helper T-cell cytokine profile. Fibrosis was characterized by a thickened ileal muscle layer, collagen deposition, and increased fibroblasts at the sites of collagen deposition. SHIP –/– ilea had increased arginase activity and arginase I expression that was inversely proportional to nitrotyrosine staining. SHIP –/– mice were treated with the arginase inhibitor S-(2-boronoethyl)- l-cysteine, and changes in the disease phenotype were measured. Arginase inhibition did not affect the number of immune cell infiltrates in the SHIP –/– mouse ilea; rather, it reduced collagen deposition and muscle hyperplasia. These findings suggest that arginase activity is a potential target to limit intestinal fibrosis in patients with CD.