Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection

Abstract

temic expansion of ST2 + Tregs (29,30). IL-33 expressed by fibrogenic/adipogenic progenitors in skeletal muscle has also been shown to regulate skeletal muscle Treg homeostasis and support muscle regeneration (31). Related studies have suggested a direct, cardioprotective role for rIL-33 against hypertrophy resulting from cardiac overload (32) and fibrosis after myocardial infarction (33). However, delivery of rIL-33 also aggravates autoimmune eosinophilic pericarditis during coxsackievirus B3 infection (34), suggesting that IL-33 can contribute to cardiac inflammation. IL-33 expression has been reported in cardiac fibroblasts (32) and the vasculature ( 35), yet how the expression of this alarmin is modulated in cardiac allografts or impacts outcomes was unknown.Using IL-33-deficient heart grafts in a mouse chronic rejection model we have established that IL-33 stands out among identified alarmins and limits differentiation of proinflammatory macrophages to prevent chronic rejection. Specifically, transplants lacking IL-33 displayed dramatically accelerated chronic rejectionassociated vasculopathy and subsequent fibrosis orchestrated by graft-infiltrating recipient proinflammatory macrophages. IL-33expressing heart grafts in recipients with ST2-deficient macrophages also displayed increased graft infiltration by proinflammatory macrophages and accelerated graft loss. Mechanistic studies demonstrated that IL-33 promoted a reparative macrophage phenotype through a metabolic reprograming involving augmented oxidative phosphorylation (OXPHOS) and fatty acid (FA) uptake. We also revealed that IL-33 prevents proinflammatory stimuli-induced disruption of the tricarboxylic acid (TCA) cycle that shifts macrophage metabolism to anaerobic glycolysis and generates proinflammatory metabolites (36,37). Restoration of IL-33 to IL-33-deficient heart transplants using vesicles in ECM-derived hydrogel immediately after transplantation profoundly reduced the frequency of proinflammatory myeloid cells in the graft and prevented graft loss to chronic rejection. Thus, the local delivery of IL-33 in ECM-based materials after transplantation may be a practical and promising biologic for chronic rejection prophylaxis.

When Alarmins Are “Therapeutic”

“…Using a mouse model of chronic rejection following heart transplant, Li et al 3 showed that the lack of IL-33 expression in the transplanted heart accelerates graft rejection, associated with increased T-cell infiltration. In light of these observations IL-33 emerges as a stromal cell-derived alarmin which limits the local inflammatory response early after transplantation (Figure).…”

“…Indeed, IL-33 is upregulated in allografts and its absence significantly aggravates vascular occlusion and subsequent fibrosis in the transplanted tissue. 3 …”

“… 3 , 4 Loss of graft IL-33 results in increased recruitment of proinflammatory macrophages expressing the inflammatory marker inducible nitric oxide synthase (iNOS). 3 , 5 Blockage of monocyte recruitment as well as hydrogel-based local IL-33 delivery to the graft reduced the number of infiltrating proinflammatory macrophages and protected against vasculopathy and fibrosis in transplanted IL33-deficient mice. 3 , 4 , 6 Importantly, these effects are achieved via local—and not systemic—IL-33 action.…”

“… 3 , 5 , 7 Although similar to IL-4–induced macrophages, IL-33–triggered macrophages reflect a unique phenotype hallmarked by a specific metabolic remodeling with aspartate-arginosuccinate shunt features, increased fatty acid uptake and reduced iNOS expression. 3 , 7 In vitro experiments demonstrated that IL-33 prime macrophages toward an “M2-like” anti-inflammatory phenotype through fatty acid uptake while limiting the induction of iNOS, which is required for a glycolytic and proinflammatory macrophage shift. 3 , 5 , 7 Consistent with these findings, fatty acid uptake in macrophages from heart transplants is significantly reduced in the absence of IL-33, supporting an important role for graft IL-33 in stimulating fatty acid–driven metabolic switch in infiltrating myeloid cells and triggering a tolerogenic response to the transplant.…”

“… 3 , 7 In vitro experiments demonstrated that IL-33 prime macrophages toward an “M2-like” anti-inflammatory phenotype through fatty acid uptake while limiting the induction of iNOS, which is required for a glycolytic and proinflammatory macrophage shift. 3 , 5 , 7 Consistent with these findings, fatty acid uptake in macrophages from heart transplants is significantly reduced in the absence of IL-33, supporting an important role for graft IL-33 in stimulating fatty acid–driven metabolic switch in infiltrating myeloid cells and triggering a tolerogenic response to the transplant. The crucial and specific role of IL-33 in driving monocyte recruitment and macrophage differentiation after transplant was definitely proven in LysM-Cre conditional mice deficient for the expression of the IL-33 receptor serum stimulation-2 in myeloid cells.…”