Dangers within: DAMP responses to damage and cell death in kidney disease

Abstract

The response to exogenous pathogens leads to activation of innate immunity through the release of pathogen-associated molecular patterns (PAMPs) and their binding to pattern recognition receptors. A classic example is septic shock where Toll receptor 4 recognizes PAMPs. Although well accepted, this concept does not explain the activation of innate immunity and inflammation occurs with transplantation, autoimmunity, or trauma. Increasingly recognized is that endogenous molecules released by dying cells (damage-associated molecular patterns; DAMPs) activate cellular receptors leading to downstream inflammation. Thus endogenous danger signals and exogenous PAMPs elicit similar responses through seemingly similar mechanisms. Also emerging is our understanding that normal repair processes benefit from dampening the immune response to these endogenous danger molecules. Here we focus on the role of DAMPs and their putative receptors in the pathogenesis of acute and chronic kidney diseases.

Figure 1.

Danger and stranger models. Infections of pathogenic bacteria or viruses cause release of PAMPs that bind to pattern recognition receptors (PRRs), such as TLRs, on immune cells and stimulate an innate immune response that is accompanied by inflammation, activation of adaptive immunity, and eventually processes to resolve the infection and allow for tissue repair. The danger model recognizes that similar events occur when cells are stressed or injured and that necrotic cells release molecules that are normally hidden within the cell. In the extracellular space these DAMPs can bind to PRRs or to specialized DAMP receptors to elicit an immune response by promoting release of pro-inflammatory mediators and recruiting immune cells to infiltrate the tissue. The immune cells that participate in these processes include, for example, APC, such as dendritic cells and macrophages, as well as T cells and neutrophils (PMN). DAMPs may also stimulate adaptive immunity and participate in autoimmune responses and tissue repair. A wide variety of intracellular and extracellular molecules function as DAMPs when released from cells (Table 1). The functions of such a diverse group of molecules may not yet be fully elucidated; it is unknown whether different DAMPs have specific roles, whether specific functions are elicited in different cell types or conditions, or even whether immune responses to DAMPs can be distinguished from those of PAMPs.

Figure 2.

Proposed mechanisms for discriminating DAMPS from PAMPs and limiting the immune response. Several groups have recently proposed mechanisms that share a common theme involving coreceptors that pair with receptors for DAMPs and PAMPs to allow cells to distinguish between these related molecules and perhaps elicit downstream immune responses that may be specific for the ligand. For simplicity, these examples are illustrated only with inflammation as the target response, but selective signaling mechanisms may also result in varied inflammatory responses and provide specificity that may or may not include activation of adaptive immunity and tissue repair processes. (1) The CD24-Siglec pathway can distinguish DAMPs from PAMPs and can suppress DAMP signaling to prevent an unrestrained immune response and excessive collateral tissue damage.^– By interacting with sialic acid-binding Ig-like lectins (Siglec-G (mouse) or Siglec-10 (human)), CD24, a glycosylphosphatidylinositol (GPI)-anchored molecule (also known as heat-stable antigen) with diverse T-cell homeostatic functions, negatively regulates the TLR- or NLR-mediated immune response to HMGB1 and heat-shock proteins but not PAMPs (LPS or poly(I:C)) perhaps by facilitating association with phosphatases, like SHP-1. (2) Others suggest that although PAMPs and DAMPs bind to some of the same receptors, interaction with different coreceptors may account for a divergence in downstream effects. (3) A mechanism for discriminating DAMPs from PAMPs has also been demonstrated for two other cell surface proteins, CD14 (which recognizes DAMPs in the absence of TLR2 and promotes both TLR2-DAMP and TLR2-PAMP responses) and myeloid differentiation protein 2 (MD2; responding to and enhancing only exogenous PAMP responses in complexes with CD14-TLR2 or CD14-TLR4), that form complexes with Toll receptors. (4) Similarly, biglycan binding and induction of a multireceptor complex with TLR2/4 and purinergic P2×4 or P2×7 receptors activates the NLRP3 inflammasome, and this complex may regulate immune cell infiltration and tissue injury in kidneys (not illustrated here).