A novel role for hepatic stellate cells in pathogenesis of visceral leishmaniasis

Potential conflict of interest: Nothing to report. See Article on Page 620 Hepatic stellate cells (HSCs) are nonparenchymal cells located at the interface between hepatocytes and liver sinusoidal endothelial cells. HSCs are quiescent under normal conditions and play an important role in the uptake and metabolism of vitamin A. Their activation by cytokines and inflammatory signals secondary to liver injury or inflammation initiates the fibrogenic process characterized by loss of vitamin A, myofibroblastic transformation, and excessive production of extracellular matrix components, notably type I collagen. In addition to their seminal role in liver fibrosis, HSCs are increasingly being recognized to have leucocyte‐like properties, including antigen presentation and immune stimulatory and regulatory functions depending on their activation status.1 HSCs express major histocompatiblity complex (MHC) class I and II and can take up and present antigens within the liver.2 They induce forkhead box protein 3 (Foxp3)+ regulatory T cells (Tregs) through production of retinoic acid, promote their expansion in an MHC II‐dependent manner, and thus contribute to immunological tolerance within the liver.4 HSCs may also interact with hepatotropic pathogens that induce their activation. In this issue of Hepatology, Khadem et al.6 explore a novel role for HSCs in immunity to visceral leishmaniasis (VL), a disease caused by the protozoan parasites, L. donovani and L. infantum, with severe pathological effects on the liver. Khadem et al. demonstrate that HSCs can be infected with L. donovani resulting in an increase in transforming growth factor beta (TGF‐β) production, a major driver for Treg induction and liver fibrosis. L. donovani infection also induced expansion of HSCs and Tregs in vivo. This expansion was dependent on the phosphoinositide 3‐kinase (PI3K) delta isoform (p110δ).6 Interestingly, the same group had previously demonstrated that mice with inactivating knock‐in mutation in the p110δ gene (p110δD910A) were resistant to VL.7 PI3K is a heterodimer of a 110‐kDa catalytic subunit (p110) and a regulatory subunit (p85) that recruits the complex to intracellular sites of tyrosine kinase activation by its Src homology 2 (SH2) domains. Activation of the PI3K pathway after binding of growth factors to their cognate receptors results in a signaling cascade leading to activation of protein kinase B (AKT), then a number of proteins involved in cellular differentiation, survival, growth, and oncogenic transformation, including mammalian target of rapamycin complex 1 (mTORC1).8 Furthermore, the PI3K pathway has been implicated in proliferation and survival of HSCs as well as downstream signaling of the fibrogenic platelet‐derived growth factor (PDGF) and TGF‐β pathways (Fig. 1). Khadem et al.6 demonstrate that HSCs express p110δ, but it is not clear how this influences their immunoregulatory properties during VL. One possibility is enhanced proliferation and survival of HSCs, resulting in their accumulation in the liver as observed in this study. An increase in the numbers of HSCs will likely translate into increased induction and proliferation of Tregs in the liver. Another possibility is that VL induces production of chemokines implicated in recruitment of Tregs to the liver. Future experiments using Foxp3 reporter mice in combination with intravital imaging could help elucidate this point. The investigators also demonstrate that Leishmania infection of HSCs results in an increase in production of immuneregulatory cytokines that favor the development of Tregs. However, the signaling pathways activated by Leishmania infection in HSCs and the link between p110δ and the increase in such cytokines and induction of Tregs remain undefined. Interestingly, unlike the previous reports, HSCs were found to produce interleukin (IL)‐2 and IL‐4, the synthesis of which increased upon Leishmania infection. It is important to note that only a subpopulation of HSCs expressed these cytokines. Given the heterogeneity in HSC population within the liver, it is likely that HSCs by themselves might induce expansion of Tregs in selective hepatic compartments. This process can also be influenced by the production of these cytokines by infiltrating and locally present non‐HSC cell types.Figure 1: The PI3K pathway has been implicated in proliferation and survival of HSCs and signaling of the fibrogenic PDGF and TGF‐β pathways. PI3K is a heterodimer of a 110‐kDa catalytic subunit (p110) and a regulatory subunit (p85) that recruits the complex to intracellular sites of tyrosine kinase activation by its SH2 domains after its activation. Leishmania infection leads to enhanced proliferation of HSCs and production of immuneregulatory cytokines in a PI3K/p110δ‐dependent manner, culminating in induction of Tregs. However, the signaling pathways activated by Leishmania infection in HSCs and the link between p110δ and the increase in such cytokines and induction of Tregs remain undefined. Abbreviations: PDGF‐R, platelet‐derived growth factor receptor; SMAD2/3, small mothers against decapentaplegic homologs 2 and 3; TGFβ‐R, transforming growth factor beta receptor;The investigators demonstrate that Leishmania infection results in higher levels of MHC class II and CD86 expression on HSCs,6 but expression of other costimulatory and inhibitory molecules, such as programmed death ligand 1, or mediators, such as indoleamine 2,3‐dioxygenase, was not examined. Another important consideration is that other liver resident cells with immune‐regulatory properties, such as monocyte‐derived suppressor cells or M2 macrophages, may be infected with Leishmania and contribute to enhancement of the tolerogenic milieu in the liver and induction and expansion of Tregs. Khadem et al. demonstrate the central role of HSCs through their depletion using the single‐chain antibody, C1‐3, conjugated to gliotoxin that binds to and depletes activated HSCs.6 This resulted in reduced numbers of Tregs in the liver, reduced IL‐10 production by hepatic T cells, and better parasite control. Although the investigators demonstrated that other immune cell subsets were not affected, a more specific inducible approach, such as Lecithin retinol acyltransferase‐Cre mice expressing Cre‐inducible diphteria toxin receptor,9 should be considered in future experiments. It will be interesting to see whether the novel mechanism described by Khadem et al. is restricted only to Leishmania infection or can be generalized to other hepatotropic pathogens. It is also tempting to speculate about a similar mechanism for nonhepatotropic pathogens, such as human immunodeficiency virus, that may infect HSCs or contribute to their activation.10 Finally, it will be important to assess the relative contribution of HSCs, as compared to other cells, such as macrophages, to induce immunological tolerance via Treg induction and expansion. Author names in bold designate shared co‐first authorship.

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