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In View: Research Highlights

Research Highlights

Singh, Prince MD1; Luo, Xunrong MD, PhD1

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doi: 10.1097/TP.0000000000003906
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IL-23 Reshapes Kidney Resident Cell Metabolism and Promotes Local Kidney Inflammation

Hao Li, Maria G. Tsokos, Rhea Bhargava, et al. J Clin Invest. 2021;131(12):e142428.

Immune-mediated kidney damage lies at the core of many kidney disorders that may broadly be classified into primary disease entities, including membranous nephropathy or focal segmental glomerulosclerosis, or systemic diseases, affecting kidneys among other organs such as lupus nephritis, infection-induced glomerulonephritis, or antineutrophil cytoplasmic antibody vasculitis.1 The prevailing consensus is that recruitment of Th1 and Th17 type effector T cells mediates progressive and sustained kidney tissue damage through the release of proinflammatory cytokines including interleukin (IL)-23, a known proinflammatory cytokine contributing to Th17 generation. How those processes may alter the function of nonlymphoid cells is entirely unknown.

Li et al2 have shown that IL-23 directly modulates the inflammatory milieu by acting on renal tubular epithelial cells (TECs). The authors demonstrated that systemic overproduction of IL-23 by hydrodynamic administration of a minicircle cDNA contract encoding IL-23 subunits led to renal inflammation inducing the calcium/calmodulin-dependent protein kinase IV (CaMK4) in TECs. This process, in turn, downregulated the arginine-hydrolyzing enzyme arginase 1 (ARG1) locally, resulting in an elevated local arginine level, thereby promoting an inflammatory milieu for T-cell proliferation and activation. Consequently, genetic deficiency of IL-23 receptor (IL-23R) or CaMK4 ameliorated renal inflammation, whereas deficiency of ARG1 augmented the process. Moreover, TEC-targeted delivery of a CaMK4 inhibitor ameliorated renal inflammation in a mouse model of lupus nephritis. To add to the translational value of these findings, the authors also demonstrated that upregulation of IL-23R and CaMK4, in addition to downregulation of ARG1, was detected in renal biopsies of patients with active lupus nephritis, antineutrophil cytoplasmic antibody–associated nephritis, and short-term rejections, but not in normal kidney tissues. Furthermore, increased expressions of IL-23R and CaMK4 with a reduced expression of ARG1 were noted on TECs but not on other renal cell types in patients with active lupus nephritis.

The efforts by Li et al are commendable as they show, for the first time, that resident TECs can respond to systemically produced IL-23, modifying the metabolism of TECs and promoting a local milieu conducive to T-cell proliferation and subsequent kidney inflammation. As monoclonal antibodies targeting various subunits of IL-23 are now clinically available, this study provides valuable mechanistic insights that could fine-tune our choice of agents tailored to target tissue inflammation. This study also emphasizes on the intriguing concept of targeting local inflammation by altering nutrients (eg, amino acids) or oxygen delivery needed for cell metabolism. With relevance to kidney transplantation, it will be interesting to learn how IL-23 signaling in allograft TECs may augment cellular and humoral alloimmunity and how TECs may respond to IL-23 neutralizing antibodies.

Non-conditioned Bone Marrow Chimeric Mouse Generation Using Culture-based Enrichment of Hematopoietic Stem and Progenitor Cells

Kiyosumi Ochi, Maiko Morita, Adam C. Wilkinson, et al. Nat Commun. 2021;12(1):3568.

In immunology and hematology research, bone marrow chimeric mice1 are frequently used as a quicker and less expensive alternative to the generation of genetically altered mice to study the function of a specific molecule. However, several limitations of this approach hinder its wider application. These are: (1) Recipient bone marrow ablation with either irradiation or chemotherapy is necessary to allow for donor bone marrow cell engraftment. This ablation not only disturbs the normal steady-state hematopoiesis, which confounds research findings, but also increases tissue toxicities, which leads to recipient morbidity and mortality. (2) Donor bone marrow cells to be used, namely donor hematopoietic stem and progenitor cells (HSPCs), require complex fluorescence-activated cell sorting–based isolation, demanding technical expertise as well as adding to expenses.

In this study, Ochi et al2 reported a novel polyvinyl alcohol–based culture system of 28 d that selectively expanded HSPCs, which were then capable of engrafting into recipients without host bone marrow ablation. In detail, the starting cell population required only simple magnetic-activated cell sorting for c-Kit+ cells and was then expanded ex vivo for 28 d in polyvinyl alcohol–based culture medium. During this culture period, c-Kit+ cell numbers increased on average 5.8-fold, and the percentage of c-Kit+Sca1+Lineage HSPCs also progressively increased from ~5.9% to ~30% on day 28 of the culture, corresponding to a lower level of expression of senescence-related genes when c-Kit+-enriched cells were used to initiate the culture. More importantly, when nonconditioned, immunocompetent mice were used as hosts, these c-Kit+-expanded HSPCs reliably achieved peripheral blood chimerism, averaging 30%–35% by 4–16 wk posttransplantation if 1 × 106 cells were initially transplanted; fresh nonexpanded c-Kit+ cells, at the same dose, were not able to achieve meaningful chimerism in nonconditioned recipients. Finally, the authors demonstrated the feasibility of genetically engineering such culture-expanded HSPCs. In this regard, they showed that lentiviral transduction could be achieved with high efficiency, demonstrated by the expression of the model gene enhanced green fluorescent protein. Moreover, culture-expanded and lentiviral-transduced HSPCs were also able to engraft nonconditioned recipients to achieve comparable peripheral blood chimerism of 22%–26% by 16 wk posttransplantation.

This work puts forth a novel and technically less cumbersome method for generating bone marrow chimeras with relevance for studies of hematopoietic and immune system biology. The ability of HSPCs expanded by this method for engraftment in nonconditioned immunocompetent mice further adds to its applicability in long-term studies where recipient toxicity needs to be minimized. Depending on the question to be addressed, it might be necessary to precisely control the degree of chimerism by genetically engineered HSPCs in the context of endogenous wild-type HSPCs in nonconditioned recipients. It will thus be interesting to understand a similar dosage response with escalating doses to determine the maximal achievable chimerism, much as the limiting dilution with decreasing doses performed in this study. In addition, elucidating mechanisms of the enhanced engraftment of culture-expanded HSPCs in comparison with fresh HSPCs will be informative and likely relevant to studies such as those in transplantation tolerance.3

REFERENCES

1. Couser WG. Basic and translational concepts of immune-mediated glomerular diseases. J Am Soc Nephrol. 2012;23:381–399.
2. Li H, Tsokos MG, Bhargava R, et al. IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation. J Clin Invest. 2021;131:e142428.

REFERENCES

1. Ferreira FM, Palle P, Vom Berg J, et al. Bone marrow chimeras—a vital tool in basic and translational research. J Mol Med (Berl). 2019;97:889–896.
2. Ochi K, Morita M, Wilkinson AC, et al. Non-conditioned bone marrow chimeric mouse generation using culture-based enrichment of hematopoietic stem and progenitor cells. Nat Commun. 2021;12:3568.
3. Hu M, Alexander SI, Yi S. Bone marrow chimerism as a strategy to produce tolerance in solid organ allotransplantation. Curr Opin Organ Transplant. 2016;21:595–602.
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