Control of infection by pyroptosis and autophagy: role of TLR and NLR

Abstract

Cells can die by distinct mechanisms with particular impacts on the immune response. In addition to apoptosis and necrosis, recent studies lead to characterization of a new pro-inflammatory form of cell death, pyroptosis. TLR and NLR, central innate immune sensors, can control infections by modulating host cell survival. In addition, TLRs can promote the induction of autophagy, thus promoting delivery of infecting pathogens to the lysosomes. On the other hand, activation of some NLR members, especially NLRC4 and NAIP5, leads to the infected cell death by pyroptosis, which is accompanied by secretion of the pro-inflammatory cytokines IL-1beta, IL-18, and IL-33. Data presented here illustrate how the compartmentalization of the innate immune sensors can influence the outcome of infections by controlling the fate of host cells.

Fig. 1

Compartmentalized innate immune sensors. TLR are transmembrane proteins that can be found at plasma membrane (TLR1, 2, 4, 5, 6, and 11) or at endosomes (TLR3, 7, 8, and TLR9). These proteins contain an extracellular domain containing leucine-rich repeat (LRR) motifs responsible for ligand recognition and a cytoplasmic Toll/interleukin-1 (IL-1) receptor (TIR) domain that recruits adaptor molecules (not represented here) thereby initiating intracellular signaling [1]. NLRs are cytosolic proteins that contain three domains: a C-terminal domain containing LRR, which is assumed to be responsible for the recognition of NLR ligands; a central NOD-like domain crucial for activation; and a diverse effector N-terminal domain, such as the caspase recruitment domain (CARD), the pyrin domain (PYD), the acidic domain, or the baculovirus inhibitor repeat (BIR) domain

Fig. 2

Proposed scheme for different forms of cell death. Apoptosis and necrosis apparently are the most distinct forms of cells death. Apoptosis is a strictly regulated process of cell death in which cells undergo some modifications that permits their silent removal by adjacent cells. These modifications include reduction of cell volume and packaging of cellular contents, DNA and nuclear fragmentation, formation of cytoplasmic and membrane blebs, and phosphatidylserine externalization. In contrast, necrotic cells increase their volume and lose the cell membrane integrity leading to the release of their cellular contents and consequent inflammation. Note that necrotic cells preserve the uncondensed DNA content. Autophagy and pyroptosis could be seen as another polarized scheme of cell death, since they have opposite consequences to the immune response. Like necrosis, pyroptosis is a highly inflammatory process in which cells also lose their cell membrane integrity. However, along with cellular contents, pyroptotic cells secrete inflammatory cytokines such as IL-1β, IL-18, and IL-33. Interestingly, the nuclear modifications observed during pyroptosis are similar to the DNA fragmentation and nuclear condensation detected in apoptosis. Similarly to apoptosis, autophagy is another silent process by which cells can undergo death. In this case, cells maintain the membrane integrity and exhibit a profound vacuolization as a result of the double-membrane composed autophagosome formation. Since autophagy and pyroptosis share some molecular characteristics with both apoptosis and necrosis, we inserted this new scheme in the middle of them. Moreover, as TLR clearly modulate autophagy and inflammasomes are the key inducers of pyroptosis, these two families of PRR are represented in cells undergoing their respective forms of cell death