Preprint Club
A cross-institutional Journal Club Initiative

Keywords

●  Adventitial fibroblast

●  Innate lymphoid cells (ILC)

●  Fibrotic disease

Main Findings

Sbierski-Kind J & Cautivo KM et al. demonstrate that IL-5+ innate lymphoid cells (ILC)2 and IL-17+ gd T cells colocalize with IL-33high adventitial fibroblasts (AF) in steady state and during cellular expansion in three separate mouse models of liver fibrosis (e.g., CCl4-induced liver fibrosis). Furthermore, the authors demonstrate that germline and inducible depletion of IL-5+ ILC2 results in expansion of IL-17A-producing gd T cells and enhances liver fibrosis, whereas concurrent depletion of IL-5+ lymphocytes and IL-17A+ lymphocytes suppresses liver inflammation and fibrosis. Taken together, this suggests IL-33high AF sustain an IL-5+ ILC2 niche which limits type 3/17-mediated liver fibrosis.

Limitations

·  The authors demonstrate that IL-33high AF and myofibroblasts are distinct populations in liver fibrosis. In addition, the authors demonstrate that lung AF were sufficient to support both ILC2 and gd T cells in the absence of cytokine supplementation or TCR stimulation ex vivo. Using myofibroblasts as a control to determine whether this capacity is unique to AF should be considered.

·  The authors demonstrate that Tregs are elevated after 18 hours, 3 weeks, and 4 weeks of CCL4-inudced liver fibrosis. Additional experiments may be useful to determine the effect of IL-5+ ILC2 depletion or concurrent deletion of type 2 and 3/17 lymphocytes on Treg populations and subsequent impact on liver fibrosis.

·  The authors demonstrate that IL-5+ ILC2 restrain Type 3/17-lymphocte expansion in CCL4- and bile-duct ligation (BDL)-induced liver fibrosis. Moreover, the authors demonstrate that concurrent deletion of type 2 and 3/17 lymphocytes results in attenuated CCL4-induced liver fibrosis. The impact of concurrent deletion of type 2 and 3/17 lymphocytes was not evaluated in BDL-induced liver fibrosis.

·  The authors demonstrate that IL-33high AF sustain ILC2 which suppress fibrosis driven by type 3/17 lymphocytes. The precise molecular mediators which govern these separate processes were not fully elucidated.

·  The ability of IL-5+ ILC2 to restrain type 3/17 lymphocyte populations in other diseases driven by type 3/17-mediated inflammation should be considered.

Significance/Novelty

The authors demonstrate that dual depletion of the dominant lymphocyte populations which inhabit the IL-33high AF niche (i.e., IL-5+ ILC2 & IL-17+ gd T cells) results in suppressed liver fibrosis. Therefore, targeting distinct fibroblast populations which maintain similar niches in fibrotic disease may represent a novel therapeutic strategy.

Credit

Reviewed by Anthony Altieri as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology, University of Oxford, and the University of Toronto. The author declares no conflict of interests in relation to their involvement in the review.