Interleukin‐6 (IL‐6) is critically involved in liver regeneration after partial hepatectomy (PHX). Previous reports suggest that IL‐6 trans‐signaling through the soluble IL‐6/IL‐6R complex is involved in this process. However, the long‐term contribution of IL‐6 trans‐signaling for liver regeneration after PHX is unknown. PHX‐induced generation of the soluble IL‐6R by ADAM (a disintegrin and metallo) proteases enables IL‐6 trans‐signaling, in which IL‐6 forms an agonistic complex with the soluble IL‐6 receptor (sIL‐6R) to activate all cells expressing the signal‐transducing receptor chain glycoprotein 130 (gp130). In contrast, without activation of ADAM proteases, IL‐6 in complex with membrane‐bound IL‐6R and gp130 activates classic signaling. Here, we describe the generation of IL‐6 trans‐signaling mice, which exhibit boosted IL‐6 trans‐signaling and abrogated classic signaling by genetic conversion of all membrane‐bound IL‐6R into sIL‐6R proteins phenocopying hyperactivation of ADAM‐mediated shedding of IL‐6R as single substrate. Importantly, although IL‐6R deficient mice were strongly affected by PHX, survival and regeneration of IL‐6 trans‐signaling mice was indistinguishable from control mice, demonstrating that IL‐6 trans‐signaling fully compensates for disabled classic signaling in liver regeneration after PHX. Moreover, we monitored the long‐term consequences of global IL‐6 signaling inhibition versus IL‐6 trans‐signaling selective blockade after PHX by IL‐6 monoclonal antibodies and soluble glycoprotein 130 as fragment crystallizable fusion, respectively. Both global IL‐6 blockade and selective inhibition of IL‐6 trans‐signaling results in a strong decrease of overall survival after PHX, accompanied by decreased signal transducer and activator of transcription 3 phosphorylation and proliferation of hepatocytes. Mechanistically, IL‐6 trans‐signaling induces hepatocyte growth factor production by hepatic stellate cells. Conclusion: IL‐6 trans‐signaling, but not classic signaling, controls liver regeneration following PHX.

The liver has an extraordinary capacity to regenerate through activation of key molecular pathways. However, central regulators controlling liver regeneration remain insufficiently studied. Here, we show that B cell-deficient animals failed to induce sufficient liver regeneration after partial hepatectomy (PHx). Consistently, adoptive transfer of B cells could rescue defective liver regeneration. B cell-mediated lymphotoxin beta production promoted recovery from PHx. Absence of B cells coincided with loss of splenic cluster of differentiation 169-positive (CD169 ) macrophages. Moreover, depletion of CD169 cells resulted in defective liver regeneration and decreased survival, which was associated with reduced hepatocyte proliferation. Mechanistically, CD169 cells contributed to liver regeneration by inducing hepatic interleukin-6 (IL-6) production and signal transducer and activator of transcription 3 activation. Accordingly, treatment of CD169 cell-depleted animals with IL-6/IL-6 receptor rescued liver regeneration and severe pathology following PHx. Conclusion: We identified CD169 cells to be a central trigger for liver regeneration, by inducing key signaling pathways important for liver regeneration.

Cytokine signaling is transmitted by cell-surface receptors that function as biological switches controlling mainly immune-related processes. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of GFP and mCherry nanobodies fused to trans-membrane and intracellular domains of cytokine receptors that phenocopy cytokine signaling induced by non-physiological homo- and heterodimeric GFP-mCherry ligands. Interleukin 22 (IL-22) signals via both IL-22 receptor α1 (IL-22Rα1) and the common IL-10R2, belongs to the IL-10 cytokine family, and is critically involved in tissue regeneration. Here, IL-22 SyCyRs phenocopied native IL-22 signal transduction, indicated by induction of cytokine-dependent cellular proliferation, signal transduction, and transcriptome analysis. Whereas homodimeric IL-22Rα1 SyCyRs failed to activate signaling, homodimerization of the second IL-22 signaling chain, SyCyR(IL-10R2), which previously was considered not to induce signal transduction, led to induction of signal transduction. Interestingly, the SyCyR(IL-10R2) and SyCyR(IL-22Rα1) constructs could to form functional heterodimeric receptor signaling complexes with the synthetic IL-6 receptor chain SyCyR(gp130). In summary, we demonstrate that IL-22 signaling can be phenocopied by synthetic cytokine receptors, identified a functional IL-10R2 homodimeric receptor complex, and uncovered broad receptor cross-talk of IL-22Rα1 and IL-20R2 with gp130.

BaCKgRoUND aND aIMS: Thrombocytopenia has been described in most patients with acute and chronic liver failure. Decreased platelet production and decreased half-life of platelets might be a consequence of low levels of thrombopoietin (TPO) in these patients. Platelet production is tightly regulated to avoid bleeding complications after vessel injury and can be enhanced under elevated platelet destruction as observed in liver disease. Thrombopoietin (TPO) is the primary regulator of platelet biogenesis and supports proliferation and differentiation of megakaryocytes. appRoaCH aND ReSUltS: Recent work provided evidence for the control of TPO mRNA expression in liver and bone marrow (BM) by scanning circulating platelets. The Ashwell-Morell receptor (AMR) was identified to bind desialylated platelets to regulate hepatic thrombopoietin (TPO) production by Janus kinase ( JAK2)/signal transducer and activator of transcription (STAT3) activation. Two-thirds partial hepatectomy (PHx) was performed in mice. Platelet activation and clearance by AMR/JAK2/STAT3 signaling and TPO production were analyzed at different time points after PHx. Here, we demonstrate that PHx in mice led to thrombocytopenia and platelet activation defects leading to bleeding complications, but unaltered arterial thrombosis, in these mice. Platelet counts were rapidly restored by up-regulation and crosstalk of the AMR and the IL-6 receptor (IL-6R) to induce JAK2-STAT3-TPO activation in the liver, accompanied by an increased number of megakaryocytes in spleen and BM before liver was completely regenerated. CoNClUSIoNS:The AMR/IL-6R-STAT3-TPO signaling pathway is an acute-phase response to liver injury to reconstitute hemostasis. Bleeding complications were attributable to thrombocytopenia and platelet defects induced by elevated PGI 2 , NO, and bile acid plasma levels early after PHx that might also be causative for the high mortality in patients with liver disease. (Hepatology 2021;74:411-427).A n adequate supply of fully functional platelets is necessary to achieve hemostasis after vascular damage. Platelet production is tightly regulated to avoid either bleeding or arterial thrombosis according to low or high platelet counts. In humans, ~10 11 platelets are daily produced and removed.

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