The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL‐33‐ and group 2 innate lymphoid cell‐dependent mechanism

Abstract

Induction of a type 2 cellular response in the white adipose tissue leads to weight loss and improves glucose homeostasis in obese animals. Injection of obese mice with recombinant helminth-derived Schistosoma mansoni egg-derived ω1 (ω1), a potent inducer of type 2 activation, improves metabolic status involving a mechanism reliant upon release of the type 2 initiator cytokine IL-33. IL-33 initiates the accumulation of group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages in the adipose tissue. IL-33 release from cells in the adipose tissue is mediated by the RNase activity of ω1; however, the ability of ω1 to improve metabolic status is reliant upon effective binding of ω1 to CD206. We demonstrate a novel mechanism for RNase-mediated release of IL-33 inducing ILC2-dependent improvements in the metabolic status of obese animals.— Hams, E., Bermingham, R., Wurlod, F. A., Hogan, A. E., O’Shea, D., Preston, R. J., Rodewald, H.-R., McKenzie, A. N. J., Fallon, P. G. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33– and group 2 innate lymphoid cell–dependent mechanism.

Contributions of innate type 2 inflammation to adipose function

“…Therefore it is difficult to know if the increased eosinophils in WAT were responsible for the reduced weight and improved glucose tolerance, or if the weight of the mouse was influenced by the systemic increases in eosinophils that occur throughout the rest of the IL-5tg mouse, which then accounted for improved glucose homeostasis. Several studies have used alternative ways to increase WAT eosinophils, such as the parasitic infection model [14,94,104,109,111,112]. Yet again, the question must be asked whether weight loss simply occurred due to the mouse being energetically taxed while clearing an infection.…”

“…To date, at least 10 primary research articles have examined the role of ILC2s in WAT homeostasis [14,16,31,94,95,112,113,115,117,119]. The initial studies used an RNase glycoprotein extracted from the Helminth egg to elicit weight loss and improve glucose tolerance associated with increased ILC2s, eosinophils, and M2-like macrophages [14].…”

“…The initial studies used an RNase glycoprotein extracted from the Helminth egg to elicit weight loss and improve glucose tolerance associated with increased ILC2s, eosinophils, and M2-like macrophages [14]. However, upon administering a deactivated form of the RNase, weight loss and glucose tolerance improvements were abolished along with inhibition of increased ILC2s and M2-like macrophages, despite eosinophils remaining elevated [14]. Thus, the elevated eosinophils in this model using a helminth extract were not necessary or sufficient to polarize macrophages and improve WAT homeostasis.…”

“…In fact, the RNase was able to act directly on adipocytes and macrophages via the mannose receptor CD206 to impart metabolic improvements (i.e. WAT beiging) [14].…”

“…This distinctive color is due to the presence of concentrated mitochondria within each brown adipocyte, accompanied by high iron concentrations required for activation of the electron transport chain during beta-oxidation. High expression of uncoupling protein 1 (UCP-1) causes this beta-oxidation to result in generation of heat rather than ATP (thermogenesis), thus assisting to maintain core body temperatures upon cold-induced activation of the sympathetic nervous system [12].Beige fat, primarily found intercalated within subcutaneous WAT, also has a characteristic darker appearance, UCP-1 expression, and fuel burning phenotype [12].Beiging, or browning as it is sometimes called, is favorable during obesity because it decreases weight and inflammation, while improving metabolic functions such as insulin sensitivity and glucose tolerance [13,14]. The presence of beige fat is most notably induced by both acute and prolonged cold exposure, and is increased in humans during colder winter months [15].…”