Alarmins, inflammasomes and immunity

Abstract

The elaboration of an effective immune response against pathogenic microbes such as viruses, intracellular bacteria or protozoan parasites relies on the recognition of microbial products called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Ligation of the PRRs leads to synthesis and secretion of pro-inflammatory cytokines and chemokines. Infected cells and other stressed cells also release host-cell derived molecules, called damage-associated molecular patterns (DAMPs, danger signals, or alarmins), which are generic markers for damage. DAMPs are recognized by specific receptors on both immune and nonimmune cells, which, depending on the target cell and the cellular context, can lead to cell differentiation or cell death, and either inflammation or inhibition of inflammation. Recent research has revealed that DAMPs and PAMPs synergize to permit secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β): PAMPs stimulate synthesis of pro-IL-1β, but not its secretion; while DAMPs can stimulate assembly of an inflammasome containing, usually, a Nod-like receptor (NLR) member, and activation of the protease caspase-1, which cleaves pro-IL-1β into IL-1β, allowing its secretion. Other NLR members do not participate in formation of inflammasomes but play other essential roles in regulation of the innate immune response.

Figure 1

TLRs and the cytosolic proteins, Nod1 and Nod2, are “pattern recognition receptors” (PRRs) that recognize microbial products called “pathogen-associated molecular patterns” (PAMPs). As a result of PRR ligation by PAMPs, proinflammatory cytokines and chemokines are synthesized and secreted.

Figure 2

DAMPs (danger signals or alarmins) are released from stressed or infected cells. The extracellular DAMPs bind to specific danger signal receptors (DAMPRs), whose ligation can lead to cell differentiation, cell death, or secretion of proinflammatory cytokines. Depending on the DAMP and the target cell, ligation of DAMPRs such as the adenosine receptor A2a can result in inhibition of inflammation.

Figure 3

Danger signals can activate an inflammasome containing an NLR, the adaptor protein ASC, and the protease caspase-1. An extracellular PAMP stimulates synthesis of pro-IL-1β, but not its secretion. Ligation of a DAMP receptor (DAMPR) with a DAMP such as extra-cellular ATP activates an inflammasome and caspase-1. Caspase-1 thus cleaves pro-IL-1β, allowing secretion of the mature cytokine. Different NLR inflammasomes detect different types of clanger: the NLRP3 inflammasome is sensitive to extracellular ATP or toxins that damage the plasma membrane, while NLRC4 is activated by cytosolic flagellin.