Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment

SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy

“…Unlike iNKT cells and adaptive lymphocytes, innate lymphoid cells lack expression of a TCR and mainly respond to cytokine cues in the milieu [122]. In particular, systemic SHIP1 pharmacological inhibition in mice increases type 2 innate lymphoid cell (ILC2) production of cytokines, suggesting a role of SHIP1 in restraining the function of these cells [123].…”

“…SHIP1 was found to be upregulated in diet‐induced obese mice [206]. SHIP1 or pan‐SHIP1/2 inhibition in diet‐induced and age‐induced obese mice reverses both obesity and hyperglycemia via eosinophil‐dependent mechanisms [123, 207]. This likely occurs via a SHIP1 inhibition‐mediated increase in IL‐4 secretion by eosinophils, which drives the polarization of macrophages to an M2‐like phenotype [123].…”

“…As suggested before [124], technical advances relying, for example, on new tools using the Cre/loxP recombination system in mice will permit better investigation of the intricacies of SHIP1 regulation in vivo-whereby such a genetic approach has already been applied for several innate immune populations [55,65,85,110], and is increasingly available for rarer immune subsets [125][126][127][128]. In particular, the role of SHIP1 in limiting type 2 responses is clear, as evidenced by its effect in macrophages, basophils, MCs, ILC2s, and eosinophils [123,124,129], possibly further increasing the relevance of SHIP1 to type 2-driven inflammation for diseases at barrier sites. SHIP1 is generally seen as a negative regulator for PI3K signaling due to its ability to reduce intracellular PI (3,4,5) P 3 levels.…”

“…SHIP1 or pan-SHIP1/2 inhibition in diet-induced and age-induced obese mice reverses both obesity and hyperglycemia via eosinophildependent mechanisms [123,207]. This likely occurs via a SHIP1 inhibition-mediated increase in IL-4 secretion by eosinophils, which drives the polarization of macrophages to an M2-like phenotype [123]. Similar results are possibly expected in humans, where SHIP1 inhibition may extend eosinophil lifespan, given the involvement of SHIP1 enzymatic activity in Siglec-8-induced eosinophil cell death [129].…”

“…Theoretically, the use of SHIP1 modulators may have either complementary or opposite effects on innate versus adaptive immune cells, where the overall outcome achieved may be difficult to assess before previous experimental validation in a complex in vivo setting, possible in dependance of the timing, dose, and route of therapy. Nevertheless, irrespective of the induced molecular events or of the relative contribution of either the innate or adaptive arms of immunity to distinct diseases, SHIP1 modulation has shown effective outcomes in animal models of airway disease [59,160], metabolic disorders [123,207], immune training [148], colitis [7], and arthritis [72,106] (Table 1). These preclinicals studies may potentially translate to clinical testing of SHIP1 modulators in these diseases.…”