Complementing the inflammasome

Abstract

The innate immune system is an ancient surveillance system able to sense microbial invaders as well as aberrations in normal cell function. No longer viewed as a static and non-specific part of immunity, the innate immune system employs a plethora of specialized pattern recognition sensors to monitor and achieve homeostasis; these include the Toll-like receptors, the retinoic acid-inducible gene-like receptors, the nucleotide-binding oligomerization domain receptors (NLRs), the C-type lectins and the complement system. In order to increase specificity and diversity, innate immunity uses homotypic and heterotypic associations among these different components. Multi-molecular assemblies are formed both on the cell surface and in the cytosol to respond to pathogen and danger signals. Diverse, but tailored, responses to a changing environment are orchestrated depending on the the nature of the challenge and the repertoire of interacting receptors and components available in the sensing cell. It is now emerging that innate immunity operates a system of 'checks and balances' where interaction among the sensors is key in maintaining normal cell function. Complement sits at the heart of this alarm system and it is becoming apparent that it is capable of interacting with all the other pathways to effect a tailored immune response. In this review, we will focus on complement interactions with NLRs, the so-called 'inflammasomes', describing the molecular mechanisms that have been revealed so far and discussing the circumstantial evidence that exists for these interactions in disease states.

Keywords: cell surface molecules; complement; inflammasome; inflammation; innate lymphoid cells.

Figure 1

Complement‐dependent inflammasome activation. Complement controls the nucleotide‐binding oligomerization domain receptor (NLR) ‘cellular emergency alarm system’: it provides Signal 1 (green arrows) for inflammasome activation by triggering pro‐interleukin‐1β IL‐1β) production via the C5a–C5aR axis, it triggers signal 2 (red arrows) either via C3a‐induced ATP release or via membrane attack complex (MAC) insertion into the membrane and Ca²⁺ fluxes. Finally, it can ‘switch off’ the alarm through C1q inhibition of caspase‐1 cleavage.

Figure 2

Complement–inflammasome interactions in chronic inflammatory conditions. Proposed mechanisms of complement‐dependent inflammasome activation in metabolic diseases (a) and neurodegenerative conditions (b). (a) In metabolic diseases, in adipocytes Toll‐like receptors (TLRs) might cooperate with (i) C5aR in response to cholesterol crystals or (ii) C5L2 in response to C3adesArg in order to provide Signal 1. Internalization of cholesterol crystals could lead to lysosomal destabilization and release of cathepsin B, providing the second signal for inflammasome activation. (b) In neurodegenerative conditions, in microglia and astrocytes: (i) TLRs might cooperate with C5aR for the recognition of amyloid or other crystalline material triggering Signal 1 of inflammasome activation or (ii) C3aR might trigger signalling and release ATP and activate the inflammasome via the P2X7 receptor. Signal 2 of inflammasome activation could be triggered by elevated cytoplasmic Ca²⁺ caused by membrane attack complex (MAC), or cathepsin B release resulting from lysosomal damage.