The inflammatory caspases: guardians against infections and sepsis

Abstract

Innate immunity is the primary host defense against invading microorganisms. Pathogen recognition, mediated through an elaborate 'microbial sensing' system comprising the Toll-like and Nod-like receptor families results in the activation of caspase-1, which is a prerequisite for pathogen clearance. Tight regulation of caspase-1 is necessary to control the magnitude of the innate immune response and protect the organism from possible damaging effects such as sepsis. Recent findings from population studies and animal models of infectious diseases and sepsis have uncovered a role for full-length caspase-12 in blocking the inflammatory response initiated by caspase-1, thus predisposing the organism to severe sepsis and sepsis-related lethality. In this review, we re-examine the relationship among the Group I caspases, their known substrates and their proposed role in apoptosis. We further discuss their function in inflammation and bacterial clearance, with an emphasis on their regulatory mechanisms during the innate immune response.

Old, new and emerging functions of caspases

“…58 In contrast to the roles of other inflammatory cytokines, caspase-12 can abrogate the inflammatory response in mice by inhibiting caspase-1, in a protease-independent function. 59 As a result, mice deficient for caspase-12 show increased bacterial clearance and resistance to sepsis. 60 Interestingly, full-length human caspase-12 protein is expressed only iñ 20% of sub-Saharan African descendants, who as a consequence exhibit weakened inflammatory and innate immune responses and increased susceptibility to sepsis.…”

The Caspase-1 Digestome Identifies the Glycolysis Pathway as a Target during Infection and Septic Shock

“…With the exception of its cytokine substrates, very little is known regarding the spectrum of cellular proteins it targets upon full activation. Similar to other caspases, caspase-1 is found in cells as an inactive precursor and is activated in response to inflammatory triggers, including pathogen-derived molecules, as well as danger signals released from infected or dying cells (2). Caspase-1 activation is achieved in a macromolecular complex known as the inflammasome through its recruitment to a scaffolding molecule generally via the adaptor ASC (3).…”

Differential Requirement of P2X7 Receptor and Intracellular K+ for Caspase-1 Activation Induced by Intracellular and Extracellular Bacteria

“…Interleukin-1␤ (IL-1␤) 3 is a key mediator of host immune responses and plays an important role in inflammatory disease, fever, and septic shock (1). The production of IL-1␤ is tightly controlled to prevent harmful effects induced by aberrant activation of IL-1 receptor signaling pathways (2,3).…”