Acute kidney injury: what part do toll-like receptors play?

Abstract

Abstract:The innate immune system plays an important role as a first response to tissue injury. This first response is carried out via germline-encoded receptors. Toll-like receptors (TLRs) are the first identified and best studied family of pattern recognition receptors. TLRs are expressed on a variety of cell types, including epithelial cells, endothelia, dendritic cells, monocytes/ macrophages, and B-and T-cells. TLRs initiate innate immune responses and concurrently shape the subsequent adaptive immune response. They are sensors of both pathogens, through the exogenous pathogen-associated molecular patterns (PAMPs), and tissue injury, through the endogenous danger-associated molecular patterns (DAMPs). TLR signaling is critical in defending against invading microorganisms; however, sustained receptor activation is also implicated in the pathogenesis of inflammatory diseases. Ischemic kidney injury involves early TLR-driven immunopathology, and the resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, the activation of TLRs also has been implicated in epithelial repair. This review focuses on the role of TLRs and their endogenous ligands within the inflammatory response of acute kidney injury.

Inflammation in AKI

“…2,5,6 Necrotic cells release damageassociated molecular patterns, such as high-mobility group box 1, histones, heat shock proteins, fibronectin, and biglycan into the extracellular spaces, which subsequently, activate pattern recognition receptors, such as toll-like receptors (TLRs), and nucleotide-binding oligomerization domain-like receptors, such as the nucleotide-binding oligomerization domain-, LRR-, and pyrin domain-containing 3 inflammasome, expressed in epithelial and endothelial cells, dendritic cells (DCs), monocytes/ macrophages, and lymphocytes. [6][7][8][9] Activated renal parenchyma cells and DCs also secrete chemokines, including CXCL1, CXCL8, CCL2, and CCL5, that promote acute neutrophil-and monocyte/ macrophage-dependent inflammatory responses in AKI. 6 , 1 0 Timedependent changes in the expression of proinflammatory (e.g., TNF-a, IFN-g, IL-6, IL-1b, IL-23, IL-17, C3, C5a, and C5b) and anti-inflammatory (e.g., IL-4, TGF-b, IL-10, heme oxygenase 1, resolvins, and protectin D1) mediators by resident and recruited cell populations are important determinants of the injury and repair phases.…”

Cytokines

“…This is sterile inflammation. The initiating trigger is followed by tissue stress and necrosis, initiating the production of pathogen-associated molecular pattern molecules (including hypoxia-inducible factor and high-mobility group box 1), inducing the upregulation of leukocyte adhesion molecules, chemokines, and TLR signaling (39). Leukocyte infiltration is rapid and significant, involving neutrophils, monocyte, macrophages, and a variety of T cells (including CD41 Th1 cells, natural killer cells, NKT cells, gd T cells, and DCs) (40).…”

Oxidative Stress and Acute Kidney Injury in Critical Illness: Pathophysiologic Mechanisms—Biomarkers—Interventions, and Future Perspectives

“…Kidney mesangial and tubular epithelial cells express TLR1, TLR2, TLR3, TLR4, and TLR6. Once a ligand is bind on the receptor, with the complicity of factors such as myeloid differentiation factor 88 (MyD88) and toll-receptor activator of interferon (TRIF), endogenous pathways are activated (nuclear factor kappa-B and mitogen-activated protein kinase pathway) and result in inflammation and interferon production [31, 34]. …”