Toll-like receptors in kidney disease

Abstract

Purpose of review: The innate immune system is our first line of defense against infection and injury, and responsible for initiating inflammatory and immune responses to resolve infections and repair injured tissues. This review focuses on the Toll-like receptors (TLRs) of the innate immune system and their role in recognizing infection and injury, and regulating inflammatory responses in the kidney.

Recent findings: There is increasing data to support a role for TLRs in immune complex-mediated glomerulonephritis. TLR7 has emerged as a key regulator of autoantibody production in murine lupus nephritis. In addition, studies have implicated TLR recognition of endogenous molecules released during cellular necrosis as critical regulators of sterile inflammation and injury. Tonic interactions between TLRs and environmental agonists derived from commensal microbes and endogenous sources may also influence autoimmune disease and inflammatory disorders affecting the kidney.

Conclusion: Future studies to decipher the contribution of TLRs and other innate immune receptors in the regulation of inflammation, immune responses, and injury in the kidney will pave the way for novel therapeutic interventions.

Figure 1. Toll-like receptor regulation of kidney disease

Toll-like receptors (TLRs) can influence kidney disease through multiple mechanisms. Local activation of TLRs by infectious agents, planted agonists (i.e. in the form of immune complexes) or the generation of endogenous agonists in the setting of injury. Systemic activation of TLRs can lead to autoantibody production, such as rheumatoid factor or lupus autoantibodies, which can be deposited in the kidney. Systemic activation can also produce inflammatory mediators that can influence preexisting disease within the kidney. Homeostatic interactions between TLRs and our environment, commensal microbes and endogenous agonists, provide tonic stimulation that influences self-nonself discrimination and basal inflammatory states.

Figure 2. Toll-like receptor signaling module

Toll-like receptors (TLRs) signal through proximal adaptors. TLR2 (+1 or 6), TLR4, TLR5, TLR7, TLR8, and TLR9 signal through MyD88 and the interleukin-1 receptor-associated kinase (IRAK) complex to activate nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinase pathways, leading to the expression of a broad set of genes involved in inflammatory responses. For TLR2 and TLR4, the Toll-interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP) is required for efficient and complete activation of this MyD88-dependent pathway. TLR7, TLR8, and TLR9 also activate IRF7 in a MyD88-dependent fashion leading to the expression of interferon-β(IFN-β) and type I IFN-associated genes. TLR3 signals through TIR domain-containing adapter-inducing IFN-β (TRIF), which activates the type I IFN response through IRF3 and also can activate NF-κB and MAP kinase pathways through receptor-interacting protein 1 (RIP1). TLR4 also engages the TRIF pathway and this is facilitated by TRIF-related adaptor molecule (TRAM). The TLRs that can activate type I IFN responses are shaded gray. Several negative regulator of TLR signaling are shown in black. Single Ig interleukin-1 receptor-related molecule (SIGIRR) is a TIR domain containing cell surface molecule that is believed to compete with TLRs for MyD88. IRAKM inhibits activation of the IRAK complex. TNFAIP3 inactivates TRAF6, blocking activation of NF-κB and MAP kinases. Activating transcription factor 3 (ATF3) binds to the promoters of some TLR-regulated genes and alters chromatin structure to affect gene expression.