Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic intestinal
inflammation and ulceration. Canada has the highest incidence of IBD in the world with 1 in
150 people affected. While treatment options target symptoms and attempt to dampen down
inflammation, an increasing population of patients is refractory to current therapeutic
options. Macrophages are heterogeneous in their functions and while it is clear that
inflammatory macrophages contribute to inflammation in IBD, multiple lines of evidence
suggest that alternatively activated macrophages may offer protection during intestinal
inflammation. In vivo SHIP deficient mouse macrophages are alternatively activated so
SHIP deficient mice provide a unique genetic model of alternative macrophage activation.
Using the dextran sodium sulfate (DSS)-induced model of colitis, I found that SHIP-/- mice
are protected during induced intestinal inflammation, the protection is macrophage mediated,
and can be conferred to a susceptible host. To determine how SHIP contributes to alternative
activation of macrophages, I demonstrate that SHIP-deficient murine macrophages are more
sensitive to IL-4-mediated skewing to an alternatively activated phenotype. Moreover, SHIP
levels are reduced in alternatively activated macrophages and this is required for alternative
activation because it is dependent on PI3K activity. Arginase (ArgI) induction is specifically
dependent on the PI3Kp110δ isoform of class IA PI3K. As such, mice deficient in
PI3Kp110δ catalytic subunit activity have increased clinical disease activity and histological
damage during DSS-induced colitis. Colitis severity correlates with reduced numbers of
ArgI+ M2 macrophages in the colon, increased nitric oxide production, and is macrophagedependent. Importantly, adoptive transfer of IL-4-treated macrophages from wild type mice,
but not from PI3Kp110δ deficient mice, protects mice during DSS-induced colitis. Protection is lost when mice are treated with inhibitors that block arginase activity showing that ArgI
activity is required for M2 macrophage-mediated protection from intestinal inflammation.
These findings identify SHIP and the PI3K pathway as critical regulators of alternative
macrophage activation and as potential targets for manipulation in IBD. In addition,
adoptive transfer of alternatively activated macrophages to patients with IBD also offers a
promising, new strategy for treatment that may be particularly useful in patients who are
refractory to conventional therapies.
