Single-cell and Bulk RNA Sequencing Highlights the Role of M1-like Infiltrating Macrophages in Antibody-mediated Rejection After Kidney Transplantation

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Mar 25

PMID 38524599

Authors

Qidan Pang

Liang Chen

Changyong An

Juan Zhou

Hanyu Xiao

Affiliations

Soon will be listed here.

Abstract

Background: Antibody-mediated rejection (ABMR) significantly affects transplanted kidney survival, yet the macrophage phenotype, ontogeny, and mechanisms in ABMR remain unclear.

Method: We analyzed post-transplant sequencing and clinical data from GEO and ArrayExpress. Using dimensionality reduction and clustering on scRNA-seq data, we identified macrophage subpopulations and compared their infiltration in ABMR and non-rejection cases. Cibersort quantified these subpopulations in bulk samples. Cellchat, SCENIC, monocle2, and monocle3 helped explore intercellular interactions, predict transcription factors, and simulate differentiation of cell subsets. The Scissor method linked macrophage subgroups with transplant prognosis. Furthermore, hdWGCNA, nichnet, and lasso regression identified key genes associated with core transcription factors in selected macrophages, validated by external datasets.

Results: Six macrophage subgroups were identified in five post-transplant kidney biopsies. M1-like infiltrating macrophages, prevalent in ABMR, correlated with pathological injury severity. MIF acted as a primary intercellular signal in these macrophages. STAT1 regulated monocyte-to-M1-like phenotype transformation, impacting transplant prognosis via the IFNγ pathway. The prognostic models built on the upstream and downstream genes of STAT1 effectively predicted transplant survival. The TLR4-STAT1-PARP9 axis may regulate the pro-inflammatory phenotype of M1-like infiltrating macrophages, identifying PARP9 as a potential target for mitigating ABMR inflammation.

Conclusion: Our study delineates the macrophage landscape in ABMR post-kidney transplantation, underscoring the detrimental impact of M1-like infiltrating macrophages on ABMR pathology and prognosis.

Citing Articles

Single-Cell RNA Sequencing in Organ and Cell Transplantation.

Abedini-Nassab R, Taheri F, Emamgholizadeh A, Naderi-Manesh H Biosensors (Basel). 2024; 14(4).

PMID: 38667182 PMC: 11048310. DOI: 10.3390/bios14040189.

References

Herriott M, Jiang H, Stewart C, Fast D, Leu R . Mechanistic differences between migration inhibitory factor (MIF) and IFN-gamma for macrophage activation. MIF and IFN-gamma synergize with lipid A to mediate migration inhibition but only IFN-gamma induces production of TNF-alpha and nitric oxide. J Immunol. 1993; 150(10):4524-31. View

Winnicki W, Sunder-Plassmann G, Sengolge G, Handisurya A, Herkner H, Kornauth C . Diagnostic and Prognostic Value of Soluble Urokinase-type Plasminogen Activator Receptor (suPAR) in Focal Segmental Glomerulosclerosis and Impact of Detection Method. Sci Rep. 2019; 9(1):13783. PMC: 6760112. DOI: 10.1038/s41598-019-50405-8. View

Malone A, Wu H, Fronick C, Fulton R, Gaut J, Humphreys B . Harnessing Expressed Single Nucleotide Variation and Single Cell RNA Sequencing To Define Immune Cell Chimerism in the Rejecting Kidney Transplant. J Am Soc Nephrol. 2020; 31(9):1977-1986. PMC: 7461682. DOI: 10.1681/ASN.2020030326. View

Sanchez-Nino M, Sanz A, Ruiz-Andres O, Poveda J, Izquierdo M, Selgas R . MIF, CD74 and other partners in kidney disease: tales of a promiscuous couple. Cytokine Growth Factor Rev. 2012; 24(1):23-40. DOI: 10.1016/j.cytogfr.2012.08.001. View

Callemeyn J, Lamarthee B, Koenig A, Koshy P, Thaunat O, Naesens M . Allorecognition and the spectrum of kidney transplant rejection. Kidney Int. 2021; 101(4):692-710. DOI: 10.1016/j.kint.2021.11.029. View

dukic N, Stromland O, Elsborg J, Munnur D, Zhu K, Schuller M . PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities. Sci Adv. 2023; 9(37):eadi2687. PMC: 10499325. DOI: 10.1126/sciadv.adi2687. View

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

Zhao Z, Yang C, Wang L, Li L, Zhao T, Hu L . The regulatory T cell effector soluble fibrinogen-like protein 2 induces tubular epithelial cell apoptosis in renal transplantation. Exp Biol Med (Maywood). 2014; 239(2):193-201. DOI: 10.1177/1535370213514921. View

Murphy E, Crean D . Molecular Interactions between NR4A Orphan Nuclear Receptors and NF-κB Are Required for Appropriate Inflammatory Responses and Immune Cell Homeostasis. Biomolecules. 2015; 5(3):1302-18. PMC: 4598753. DOI: 10.3390/biom5031302. View

10.

Li J, Basler M, Alvarez G, Brunner T, Kirk C, Groettrup M . Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation. Kidney Int. 2017; 93(3):670-680. DOI: 10.1016/j.kint.2017.09.023. View

11.

de Miranda B, Gelmini G, Risti M, Hauer V, da Silva J, Roxo V . HLA-E genotyping and its relevance in kidney transplantation outcome. HLA. 2020; 95(5):457-464. DOI: 10.1111/tan.13806. View

12.

Jose M, David J, Atkins R, Chadban S . Blockade of macrophage migration inhibitory factor does not prevent acute renal allograft rejection. Am J Transplant. 2003; 3(9):1099-106. DOI: 10.1034/j.1600-6143.2003.00188.x. View

13.

Shaw B, Cheng D, Acharya C, Ettenger R, Lyerly H, Cheng Q . An age-independent gene signature for monitoring acute rejection in kidney transplantation. Theranostics. 2020; 10(15):6977-6986. PMC: 7295062. DOI: 10.7150/thno.42110. View

14.

Arnold M, Kainz A, Hidalgo L, Eskandary F, Kozakowski N, Wahrmann M . Functional Fc gamma receptor gene polymorphisms and donor-specific antibody-triggered microcirculation inflammation. Am J Transplant. 2018; 18(9):2261-2273. DOI: 10.1111/ajt.14710. View

15.

Kawakami T, Lichtnekert J, Thompson L, Karna P, Bouabe H, Hohl T . Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions. J Immunol. 2013; 191(6):3358-72. PMC: 3808972. DOI: 10.4049/jimmunol.1300342. View

16.

Morabito S, Reese F, Rahimzadeh N, Miyoshi E, Swarup V . hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data. Cell Rep Methods. 2023; 3(6):100498. PMC: 10326379. DOI: 10.1016/j.crmeth.2023.100498. View

17.

Karczewski J, Karczewski M, Wiktorowicz K . Pretransplant urine cytokine pattern predicts acute kidney rejection. Cytokine. 2010; 51(1):10-1. DOI: 10.1016/j.cyto.2010.03.013. View

18.

Gao Y, Xu W, Guo C, Huang T . GATA1 regulates the microRNA‑328‑3p/PIM1 axis via circular RNA ITGB1 to promote renal ischemia/reperfusion injury in HK‑2 cells. Int J Mol Med. 2022; 50(2). PMC: 9242654. DOI: 10.3892/ijmm.2022.5156. View

19.

Zimmerman K, Bentley M, Lever J, Li Z, Crossman D, Song C . Single-Cell RNA Sequencing Identifies Candidate Renal Resident Macrophage Gene Expression Signatures across Species. J Am Soc Nephrol. 2019; 30(5):767-781. PMC: 6493978. DOI: 10.1681/ASN.2018090931. View

20.

Sikorski K, Czerwoniec A, Bujnicki J, Wesoly J, Bluyssen H . STAT1 as a novel therapeutical target in pro-atherogenic signal integration of IFNγ, TLR4 and IL-6 in vascular disease. Cytokine Growth Factor Rev. 2011; 22(4):211-9. DOI: 10.1016/j.cytogfr.2011.06.003. View