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Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal
Jeffrey Damman1, Mohamed R Daha, Willem J van Son
1Surgery Nephrology, University Medical Center Groningen, Groningen, The Netherlands Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. j.damman@chir.umcg.nl
Abstract:
Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia-reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia-reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered.
Insights
Innate immunity pathways, complement and Toll-like receptors (TLRs), are crucial in kidney transplant injury. Their crosstalk, potentially mediated by MAPKs, impacts outcomes, especially after donor brain death and ischemia-reperfusion.
Area of Science:
- Immunology
- Transplantation Biology
- Renal Pathology
Background:
- Innate immunity pathways, complement and Toll-like receptors (TLRs), are implicated in kidney transplant injury.
- Crosstalk between complement and TLR signaling pathways is increasingly recognized.
- Mitogen-activated protein kinases (MAPKs) may link these pathways.
Purpose of the Study:
- To review the role of complement and TLRs in renal injury during kidney transplantation.
- To explore the crosstalk between complement and TLRs in the context of donor brain death (BD) and ischemia-reperfusion injury (IRI).
- To consider future therapeutic strategies targeting these pathways.
Main Methods:
- Literature review focusing on innate immunity in kidney transplantation.
- Analysis of studies investigating complement activation and TLR signaling in renal injury models.
- Examination of evidence for crosstalk between complement and TLR pathways.
Main Results:
- Complement and TLRs are key mediators of renal ischemia-reperfusion injury (IRI).
- Donor brain death (BD) upregulates complement C3 and TLR4, detrimentally affecting allograft outcomes.
- Kidney recipients benefit from kidneys of donors with specific TLR4 genotypes (Asp299Gly/Thr399Ile).
Conclusions:
- Complement and TLRs, along with their crosstalk, significantly contribute to renal injury in kidney transplantation.
- Targeting complement and TLR activation presents a promising avenue for improving kidney transplant outcomes.
- Understanding these innate immune mechanisms is vital for developing novel therapeutic interventions.
