The innate immune system, by using germ-line encoded pattern recognition receptors (PRRs), can recognize a wide range of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) upon microbe infection. Classic examples of PRRs include toll-like receptors (TLRs) and NOD-like receptors (NLRs). Recognition of PAMPs and DAMPs triggers the formation of multi-protein complex inflammasomes, which then activates caspases to initiate<unk> . The inflammasome pathway may be canonical or noncanonical, with the former using caspase-1-activating inflammasomes and the latter using other caspases. The canonical inflammasome pathway In the canonical inflammasome pathway, PAMPs and DAMPs are recognised by certain endogenous PRRs. For example, NLR proteins NLRC4 can recognise flagellin and type III secretion system components. NLRP3 is activated by cellular events induced by different PAMPs and DAMPs stimuli. Some non-NLR proteins like absent in melanoma 2 (AIM2) and pyrin can also be activated and form inflammasomes. Also, non-inflammasome-forming PRRs such as TLRs, NOD1 and NOD2 also play important roles in<unk> . These receptors upregulate expression of inflammatory cytokines such as IFN α/β, tumour necrosis factor (TNF), IL-6 and IL-12 through NF-κB and MAPK-signaling pathways. In addition, pro-IL-1β and pro-IL-18 is released to be processed by cysteine-mediated caspase-1. The formation of NLRP3 inflammasome Canonical inflammasomes mostly contain three components: a sensor protein (PRRs), an adaptor (ASC) and an effector (caspase-1). Generally, inflammasome-forming NLR proteins share a similar structure, several leucine-rich repeat (LRR) domains, a central nucleotide-binding and oligomerization domain (NBD) and an N-terminal pyrin domain (PYD). NLRP3, for example, recruits ASC adaptor protein via PYD-PYD interaction. Both pro-caspase-1 and ASC contain a caspase activation and recruitment domain (CARD), and this homotypic CARD-CARD interaction enables autocatalytic cleavage and reassembly of procaspase-1 to form active caspase-1. Alternatively, NLRC4 can directly recruit pro-caspase-1, as it has a CARD domain instead of a pyrin domain. Activated caspase-1 is responsible for cleavage of pro-IL-1β and pro-IL-18. These cytokines, once processed, will be in their biologically active form ready to be released from the host cells. In addition, caspase-1 also cleaves the cytosolic gasdermin D (GSDMD). GSDMD can be cleaved to produce an N-terminal domain (GSDMD-N) and a C-terminal domain (GSDMD-C). GSDMD-N can oligomerize and form transmembrane pores that have an inner diameter of 10-14 nm. The pores allow secretion of IL-1β and IL-18 and various cytosolic content to extracellular space, and they also disrupt the cellular ionic gradient. The resulting increase in osmotic pressure causes an influx of water followed by cell swelling and bursting. Notably, GSDMD-N is autoinhibited by GSDMD C-terminal domain before cleavage to prevent cell lysis in normal conditions. Also, GSDMD-N can only insert itself into the inner membrane with specific lipid compositions, which limits its damage to neighbour cells. The noncanonical inflammasome pathway The noncanonical inflammasome pathway is initiated by binding of lipopolysaccharide (LPS) of gram-negative bacteria directly onto caspase-4/5 in humans and caspase-11 in murines. Binding of LPS onto these caspases promotes their oligomerization and activation. These caspases can cleave GSDMD to release GSDMD-N and trigger<unk> . In addition, an influx of potassium ions upon membrane permeabilization triggers activation of NLRP3, which then leads to formation of NLRP3 inflammasome and activation of caspase-1. These processes facilitate the cleavage of GSDMD and promote the maturation and release of pro-inflammatory cytokines. Overview of<unk>  pathways Caspase-3-dependent pyroptotic pathway An alternative pathway that links apoptosis and<unk>  has been recently proposed. Caspase-3, an executioner caspase in apoptosis, can cleave gasdermin E (GSDME) to produce a N-terminal fragment and a C-terminal fragment in a way similar to GSDMD cleavage. When apoptotic cells are not scavenged by macrophages, GSDME expression is then upregulated by p53. GSDME is then activated by caspase-3 to form pores on the cell membrane. It has also been found that GSDME can permeabilise mitochondrial membranes to release cytochrome c, which further activates caspase-3 and accelerates GSDME cleavage. This positive feedback loop ensures that programmed cell death is carried forward.
Pyroptosis
Gastroptosis
Nephroptosis
Periocular injection
Enophthalmos
Lagophthalmos
Exophthalmos
Cryptophthalmos