Cytokine-mediated, organ-specific immune modulation and dysregulation of innate lymphocytes in sepsis.

Sepsis is a life-threatening condition that is marked by dysregulated host immune responses that can induce multiorgan dysfunction. Recent evidence suggests that this immunopathology involves tissue-resident innate lymphocytes, including innate-lymphoid cells (ILCs) and innate-like lymphocytes (ILLs). This review elucidates the organ-specific roles of the three ILC groups (ILC1s, ILC2s, and ILC3s) and two ILL types (NKT and γδ T cells) in sepsis, particularly their cytokine-mediated functions and cell-cell interactions. The literature shows that in the lungs, ILC2-derived IL-9 and IL-13 mitigate pulmonary inflammation and preserve endothelial integrity but dysregulated ILC2 activation may exacerbate injury. In the heart, ILC2s may mediate cardioprotective effects by inducing IL-13-STAT3 signaling and IL-5-mediated eosinophil recruitment. Kidney-resident ILC2s may promote tissue repair in acute-kidney injury (AKI) but their role in sepsis-associated AKI remains underexplored. In the gut and liver, ILC3s protect from sepsis via IL-22, which promotes barrier integrity, but they can convert into ILC1s, whose IFN-γ contributes to tissue damage. Circulating NK cells may play pathogenic and beneficial roles at different times after sepsis onset. NKT and γδ T cells are respectively protective and pathogenic in the gut and liver, likely through their respective production of IFN-γ and IL-17 A. Thus, ILCs and ILLs play key roles in sepsis and could be potential therapeutic targets. Further research is needed to elucidate their precise contributions in each organ and how time since onset and local and systemic conditions affect these contributions.