RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock

Abstract

BackgroundType 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated.ObjectiveTo investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model.MethodsCirculating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well.ResultsThe number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS.ConclusionsThese results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.

A crosstalk between type 2 innate lymphoid cells and alternative macrophages in lung development and lung diseases (Review)

“…ILC2s express corresponding receptors, including suppression of tumorigenicity 2 (ST2), IL-25R (IL-17RB), TSLPR and AREG receptor, as well as toll-like receptors (TLRs) 2 and 4 ( 28 , 29 , 43 – 45 ). Upon activation, excluding Th2-type cytokines and/or AREG, ILC2s also secrete other factors, including granulocyte-macrophage colony stimulating factor (GM-CSF), IL-6 and IL-10 ( 46 – 48 ).…”

The Role of Innate Lymphoid Cells in the Regulation of Immune Homeostasis in Sepsis-Mediated Lung Inflammation

“…Meanwhile, an excessive ILC2 immune response can cause aggravating type 2 lung inflammation. For instance, high-mobility group box 1 promotes lung ILC2 proliferation and decreases ILC2 apoptosis following hemorrhagic shock, leading to the accumulation of ILC2 in the lung [ 55 ]. This leads to eosinophil infiltration and type 2 cytokine production in the lung, thereby contributing to lung injury following hemorrhagic shock [ 55 ].…”

“…For instance, high-mobility group box 1 promotes lung ILC2 proliferation and decreases ILC2 apoptosis following hemorrhagic shock, leading to the accumulation of ILC2 in the lung [ 55 ]. This leads to eosinophil infiltration and type 2 cytokine production in the lung, thereby contributing to lung injury following hemorrhagic shock [ 55 ]. Therefore, analyzing the immunological dynamics of ILC2s in sepsis, which cause a dysfunctional immune response to infection, could lead to new insights into the pathophysiology of sepsis-induced lung inflammation.…”

Activation of NLRP3 inflammasome up-regulates TREM-1 expression in murine macrophages via HMGB1 and IL-18

“…NLRP3 inflammasome is a cytoplasmic receptor and mediates the release of pro-inflammatory cytokines, such as IL-1β, IL-18, and HMGB1 [20] , [21] . Elevated IL-18 and HMGB1 occur in ALI patients and have been associated with a poor long-term prognosis in ALI [22] , [23] . NLRP3 inflammasome has emerged as a novel strategy for the prevention and treatment of ALI [24] .…”