Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis

Abstract

Group 2 innate lymphoid cells (ILC2) are one of three subgroups of innate lymphoid cells (ILC1, ILC2, and ILC3), and the major ILC population detected in the lungs. The function of ILC2 in the regulation of lung inflammation remains unclear. In the current study, we explored an important role of ILC2 in protecting lung endothelial cell (EC) from pyroptosis in sepsis-induced acute lung inflammation and the underlying mechanism. Using a cecal ligation and puncture (CLP) mouse sepsis model, we demonstrated that IL-33, which is released in response to sepsis, acting through its receptor ST2 mediates ILC2 expansion in the lungs. We further showed that the increased ILC2 in the lungs secrete IL-9, which in turn prevents lung EC from undergoing pyroptosis, a pro-inflammatory cell death form, by attenuating caspase-1 activation. These findings suggest a previously unidentified innate pathway that negatively regulates lung inflammation following sepsis.

Tissue‐resident innate immunity in the lung

“…The tissue restorative functions of ILC2s were attributed to amphiregulin and its production by ILC2s was found to be increased in the lungs of mice with helminth infection. 77 ILC2s may also limit tissue damage through secretion of IL-9, which protects against endothelial cell death, limits lung inflammation during sepsis, 78 and stimulates ILC2s to secrete IL-13 and IL-5 in an autocrine loop. 79 ILC2s are the main secretors of IL-9 in the lung, and IL-9 receptor expression on ILC2s is required for their engagement in tissue repair following lung damage, including secretion of amphiregulin.…”

Pulmonary group 2 innate lymphoid cells: surprises and challenges

“…67,68 Emerging anti-inflammatory role for ILC2s ILC2s are well known inducers of type-2 inflammatory responses, but recent evidence indicates that they are also involved in the resolution of inflammation and prevention of cell death through IL-9. 69,70 ILC2s are the dominant source of IL-9 during the resolution of arthritis and IL-9 + ILC2s were located in close proximity to regulatory T (Treg) cells in inflamed synovium. 69 In the absence of IL-9, ILC2-induced proliferation and activation of Tregs was impaired leading to chronic arthritis.…”

“…69,71 In a mouse cecal and ligation puncture model, sepsis induced IL-33 release and subsequent expansion of IL-9-secreting ILC2 in the lung, which prevented lung endothelial cell pyroptosis by attenuating caspase-1 activation. 70 Autocrine production of IL-9 supports ILC2 responses that co-ordinate epithelial cell maintenance and lung homeostasis. 72 Collectively, these data indicate a pivotal role for ILC2s in resolving chronic inflammation, and the potential for their therapeutic manipulation.…”

Roles of pyroptosis in myocardial ischemia/reperfusion injury diseases

“…It showed that the increased ILC2 secreting IL-9 in the lungs prevents lung ECs from undergoing pyroptosis by attenuating a caspase-1 activation. 21 Systemic exposure pulmonary tissue to the bacterial endotoxin LPS contributes to the development of fulminant pulmonary edema and acute lung injury (ALI) owing to severe endothelial pyroptosis that is dependent on the inflammatory caspases, the murine homolog a caspase-11 in mice in vivo, or caspases 4/5 in human ECs. 22 In other words, the non-canonical pathway also plays a part in endothelial pyroptosis.…”