Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice

Abstract

Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORα/GATA3 and Tie2/RORα mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13 ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.

A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2–mediated inflammation

“…Accordingly, in vivo ILC2 accumulation by IL-25 overexpression strongly induced Ccl1 transcripts in WT mice. By contrast, ILC2-deficient Tie2 cre Rora fl/sg mice (Omata et al, 2018) did not display Ccl1 mRNA induction upon IL-25 treatment ( Fig. 4 D).…”

Pulmonary group 2 innate lymphoid cells: surprises and challenges

“…69 A more recent study demonstrated that artificially increasing ILC2s significantly attenuated experimental arthritis in an IL-4/13-dependent manner. 71 Clinical relevance was demonstrated in remitting rheumatoid arthritis patients who had high numbers of ILC2s and IL-9 + ILC2s in their joints and circulation that inversely correlated with disease severity. 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.…”

“…71 Clinical relevance was demonstrated in remitting rheumatoid arthritis patients who had high numbers of ILC2s and IL-9 + ILC2s in their joints and circulation that inversely correlated with disease severity. 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.…”

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

“…Furthermore, RANKL expression was detected on a fraction of the ILC1s suggesting a possible role of ILCs to directly contribute to inflammatory osteolysis (Kindstedt et al., ). However, considering that reduction of ILC2s in mice worsened serum‐induced arthritis and collagen‐induced arthritis, and that increasing ILC2 numbers in these models diminished arthritis, ILC2s have anti‐inflammatory functions (Omata et al., ). In line with these observations, ILC2s can support resolution of inflammation by targeting eosinophils and the activation of regulatory M2‐like macrophages (Molofsky et al., ).…”