How the Innate Immune System Senses Trouble and Causes Trouble

Abstract

The innate immune system is the first line of defense in response to nonself and danger signals from microbial invasion or tissue injury. It is increasingly recognized that each organ uses unique sets of cells and molecules that orchestrate regional innate immunity. The cells that execute the task of innate immunity are many and consist of not only "professional" immune cells but also nonimmune cells, such as renal epithelial cells. Despite a high level of sophistication, deregulated innate immunity is common and contributes to a wide range of renal diseases, such as sepsis-induced kidney injury, GN, and allograft dysfunction. This review discusses how the innate immune system recognizes and responds to nonself and danger signals. In particular, the roles of renal epithelial cells that make them an integral part of the innate immune apparatus of the kidney are highlighted.

Keywords: immunology; immunology and pathology; renal tubular epithelial cells.

Figure 1.

Location and signaling pathways of pattern recognition receptors. Toll-like receptors (TLRs) are membrane-bound glycoproteins and consist of a functional homomer (e.g., TLR4) or heteromer (e.g., Toll/IL-1 receptor [TLR] 1:TLR2). TLRs have characteristic ligand-binding motifs (leucine-rich repeats and cysteine-rich repeats) and cytoplasmic signaling domains (TIR homology domains). Note the differential localization of TLRs. Upon activation of TLRs, the TIR domain engages the adaptor molecule MyD88, with the exception of TLR3, which exclusively signals through TRIF. The TIR domain of TLR4 can engage both MyD88 and TRIF pathways. The coreceptor CD14 facilitates internalization of TLR4 and subsequently activates TRIF signaling pathway. The best-characterized cytosolic receptor is the NLRP3 inflammasome complex. The mature inflammasome activates caspase-1, which in turn generates IL-1β and IL-18. These cytokines induce various proinflammatory pathways, including programmed inflammatory cell death (pyroptosis). CpG DNA, unmethylated cytosine-phosphate-guanine DNA; DAMPs, damage-associated molecular patterns; dsRNA, double-stranded RNA; IRF, IFN regulatory factor; MAL, MyD88-adapter–like; MyD88, myeloid differentiation primary response gene 88; NLRP3, NOD-like receptor family, pyrin-domain-containing 3; ssRNA, single-stranded RNA; TRAM, Toll-like receptor 4 adapter protein; TRIF, TIR domain–containing adapter-inducing INF-β.

Figure 2.

Innate immune responses encountered by microbes. Microbes are detected by pattern recognition receptors (PRRs) expressed in innate immune cells, such as macrophages.The detection of microbes by the PRRs rapidly activates signaling cascades and generates inflammatory responses. Microbial encounter also leads to maturation of macrophages and dendritic cells into antigen presenting cells. PAMP, pathogen-associated molecular pattern; TCR, T-cell receptor.

Figure 3.

A model of endotoxin-induced tubular injury. Endotoxin, released from bacteria in various molecular sizes, can be filtered through nephrons and internalized by S1 proximal tubules through a Toll-like receptor 4–dependent mechanism. The interaction between endotoxin and S1 can result in oxidative stress and injury in downstream tubular segments. Yellow lightning bolts represent signaling molecules released by macrophages or S1 cells after interacting with endotoxin.