Activation of HMGB1–TLR4 Pathway and Inflammasome Contribute to Enhanced Inflammatory Response in Extended Criteria and Kidneys With KDPI ≥85%

Abstract

Background. Metrics for evaluating low-quality kidneys have failed to predict outcomes or reduce the kidney refusal and discard rates. Kidneys from extended-criteria donors (ECDs) and kidneys with ≥85% kidney donor profile indexes (KDPIs) might have different sensitivities to the proinflammatory milieu generated by brain death. We aimed to identify gene expression profile differences in innate immunity pathways between low-quality and ideal kidneys. Methods. Preimplantation kidney biopsies from ECD (n = 41) and standard-criteria donor (n = 39) were evaluated for real-time quantitative polymerase chain reaction gene expression using the TaqMan Gene Expression Array Plates system for genes Toll-like receptor-4 (TLR4), high-mobility group box 1, nuclear factor kappa beta, myeloid differentiation primary response 88, interferon (IFN)-γ, interleukin (IL)1-β, tumor necrosis factor alpha, caspase-1 (CASP1), intercellular adhesion molecule 1, IL-10, heme oxygenase 1 hypoxia-inducible factor 1 (HIF-1), monocyte chemotactic protein 1, transforming growth factor beta 1, TIR-domain containing adapter inducing interferon-β (TRIF), TRIF-related adaptor molecule, interferon regulatory factor 3 (IRF-3), receptor-interacting protein 1, IFNβ-1, and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex. Gene expression was also evaluated in kidneys with KDPI ≥85. Results. ECD biopsies showed significantly higher expression of IL-10, TLR4, high-mobility group box 1, IFN-γ, TRIF-related adapter molecule, IRF-3, HIF-1, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex, CASP1, and IL-1β (P < 0.05) compared with standard-criteria donor biopsies. IRF-3, HIF-1, and CASP1 were exclusively upregulated in ECD kidneys. Compared with kidneys with KDPIs <85%, kidneys with KDPIs ≥85% had very similar gene transcripts as those observed in ECD kidneys, except that tumor necrosis factor alpha and monocyte chemotactic protein 1 expression was only elevated in kidneys with KDPIs ≥85%. Significant positive correlations were found between the different genes upregulated and the increase in KDPIs. Conclusions. Our results showed that TLR4 and inflammasome pathways are enhanced in low-quality kidneys and suggest that blocking of some targets might improve transplant outcomes and reduce discard rates.

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

“…In particular, IFN is effective in promoting HMGB1 release in the bloodstream during gram-negative infection [ 254 ]. Both HMGB1 and IFN are related to the release of inflammatory cytokines, especially during hypoxia [ 255 ], and concur in sustaining inflammation via the TLR4/MyD88/NF- κ B inflammatory signal pathway [ 256 , 257 ]. IFN has a role also in modulating autophagy, necessary for viral cleavage [ 258 ].…”

Involvement of Inflammasome Components in Kidney Disease

“…Gene expression of IL-1β was significantly higher in ECD renal tissue [ 194 ]. Another study found a significantly increased gene expression of NLRP3, caspase-1 and IL-1β in ECD compared to non-ECD kidney biopsies obtained immediately before kidney implantation [ 195 ].…”

The Effects of Free Heme on Functional and Molecular Changes During Ex Vivo Normothermic Machine Perfusion of Human Kidneys

“…In agreement with the NanoString transcriptomic data, there was a significant upregulation of IL-6, FOS and JUN. We also measured HMGB1, a nuclear protein that in situations of stress and ischemia, translocates from the nucleus to the cytoplasm and is excreted into the extracellular space to act as a DAMP ( 21 , 22 ). HMGB1 has proinflammatory interactions with downstream receptors such as toll like receptor-4 (TLR4).…”