REVIEWThe innate immune response in ischemic acute kidney injury
Introduction
Acute kidney injury is associated with prolonged hospitalization, higher morbidity and mortality [1]. Ischemia reperfusion injury is a leading cause of acute kidney injury in both transplanted and native kidneys. Ischemia reperfusion-induced acute kidney injury is associated with tubulointerstitial inflammation and a robust inflammatory response to hypoxia and the process of reperfusion [2], [3]. In this review, we will discuss the role of the innate immune system in ischemic acute kidney injury, as well as present recent data on a modulatory role for lymphocytes.
In ischemic acute kidney injury, hypoxic and anoxic cell injuries occur early during the ischemic phase, followed by inflammatory responses in the reperfusion phase (Fig. 1). During reperfusion, blood containing innate immune component flows through ischemic tissues and accentuates injury. It is well established that a robust inflammatory reaction occurs following ischemia reperfusion [3]. Renal ischemia reperfusion induces renal synthesis or activation of pro-inflammatory cytokines and chemokines, and recruits leukocytes into the post-ischemic kidneys—to be reviewed in more detail in following sections. Several reports demonstrating the reno-protective effects of therapy targeting innate immune components such as complements, chemokines (discussed in the following section), or adhesion molecules [4], [5], [6], directly support the role of innate immunity in the pathogenesis of acute kidney injury. Functional impairment of kidney during acute kidney injury, leading to retention of fluids and nitrogenous waste products, further aggravates and sustains inflammation.
The initiation signals activating the innate immune system as well as triggering inflammatory response can be classified into 4 categories: 1) factors passively released from injured cells, 2) factors actively synthesized and secreted from the cells that have undergone ischemia, 3) recognition of altered or injured cell structures, and 4) decreased expression of anti-inflammatory factors by injured cells [7]. In acute kidney injury, both endothelium and tubular epithelium participate in innate immune responses. The signaling responses in tubular epithelium during renal injury, such as signaling through toll-like receptors (TLRs), is quite similar with that during ascending urinary infection [8].
Section snippets
Soluble molecules and membrane-associated receptors
The innate immune response includes soluble molecules such as complement and cytokines. In order to initiate and generate a full-blown innate immune response, TLRs appear required. We will review their roles in ischemic acute kidney injury in this section.
Cellular mediators of innate immunity
Macrophages, neutrophils, natural killer (NK) cells, and dendritic cells are important cells involved in innate immune responses (Table 1). In addition, newer data also implicates lymphocytes during these early injury responses.
Other leukocytes participating in early injury responses (“innate-like”)
There are several minor lymphocytes subsets which express receptors with very limited diversity and do not undergo clonal expansion before responding effectively to the antigens. Therefore, they are known as innate-like lymphocytes (ILLs). Three main classes of ILLs are NK T cells, intraepithelial γδ T cells, and B-1 subset of B cells (B-1 cells) (Table 2).
Conclusion
Robust early inflammatory responses occur in post-ischemic kidneys, facilitating the full expression of tissue damage and organ dysfunction in acute kidney injury. Numerous experimental studies have revealed the importance of innate immune responses following ischemia reperfusion injury. Based on this information about the role of immune component of ischemic acute kidney injury, there is an opportunity to further dissect the underlying mechanisms. It will be important to study how early immune
Acknowledgments
The authors thank Dr. Maria-Teresa Gandolfo for helpful suggestions with manuscript. HR is supported by the US National Institutes of Health and US National Kidney Foundation.
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