Related Experiment Video
Updated: Jul 10, 2025
Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Non-Canonical Inflammasome Pathway: The Role of Cell Death and Inflammation in Ehrlichiosis
Aditya Kumar Sharma1, Nahed Ismail1
1Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
Abstract:
Activating inflammatory caspases and releasing pro-inflammatory mediators are two essential functions of inflammasomes which are triggered in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). The canonical inflammasome pathway involves the activation of inflammasome and its downstream pathway via the adaptor ASC protein, which causes caspase 1 activation and, eventually, the cleavage of pro-IL-1b and pro-IL-18. The non-canonical inflammasome pathway is induced upon detecting cytosolic lipopolysaccharide (LPS) by NLRP3 inflammasome in Gram-negative bacteria. The activation of NLRP3 triggers the cleavage of murine caspase 11 (human caspase 4 or caspase 5), which results in the formation of pores (via gasdermin) to cause pyroptosis. Ehrlichia is an obligately intracellular bacterium which is responsible for causing human monocytic ehrlichiosis (HME), a potentially lethal disease similar to toxic shock syndrome and septic shock syndrome. Several studies have indicated that canonical and non-canonical inflammasome activation is a crucial pathogenic mechanism that induces dysregulated inflammation and host cellular death in the pathophysiology of HME. Mechanistically, the activation of canonical and non-canonical inflammasome pathways affected by virulent Ehrlichia infection is due to a block in autophagy. This review aims to explore the significance of non-canonical inflammasomes in ehrlichiosis, and how the pathways involving caspases (with the exception of caspase 1) contribute to the pathophysiology of severe and fatal ehrlichiosis. Improving our understanding of the non-canonical inflammatory pathway that cause cell death and inflammation in ehrlichiosis will help the advancement of innovative therapeutic, preventative, and diagnostic approaches to the treatment of ehrlichiosis.
Insights
Non-canonical inflammasomes and caspases (excluding caspase 1) drive severe ehrlichiosis by causing inflammation and cell death, often due to blocked autophagy during Ehrlichia infection. Understanding these pathways is key for new treatments.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Inflammasomes are critical immune sensors activated by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs).
- Canonical inflammasome activation leads to caspase 1 activation, cleaving IL-1β and IL-18, while non-canonical pathways involve caspase 11 (caspase 4/5 in humans) and gasdermin-mediated pyroptosis.
- Ehrlichia infection causes human monocytic ehrlichiosis (HME), a severe disease linked to dysregulated inflammation and cell death via inflammasome activation, often due to impaired autophagy.
Purpose of the Study:
- To review the critical role of non-canonical inflammasomes in ehrlichiosis pathogenesis.
- To elucidate the contribution of caspase-mediated pathways (excluding caspase 1) to severe and fatal ehrlichiosis.
- To highlight the impact of blocked autophagy on inflammasome activation in Ehrlichia infection.
Main Methods:
- Literature review focusing on inflammasome pathways, caspases, and Ehrlichia infection.
- Analysis of mechanisms linking non-canonical inflammasome activation to pyroptosis and inflammation.
- Exploration of the role of autophagy blockade in Ehrlichia-induced inflammasome activation.
Main Results:
- Virulent Ehrlichia infection activates both canonical and non-canonical inflammasome pathways, contributing to HME pathophysiology.
- Non-canonical inflammasome activation, involving caspase 11 (caspase 4/5), leads to pyroptosis and inflammation.
- Impaired autophagy is a key mechanism underlying inflammasome activation in Ehrlichia-infected cells.
Conclusions:
- Non-canonical inflammasomes and specific caspase pathways are central to the severe inflammation and cell death observed in ehrlichiosis.
- Targeting these non-canonical inflammatory pathways offers potential for developing novel therapeutic and diagnostic strategies for HME.
- Further research into the interplay between Ehrlichia, autophagy, and non-canonical inflammasomes is crucial for advancing HME treatment.
Related Concept Videos
01:17The Extrinsic Apoptotic Pathway
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:31The Intrinsic Apoptotic Pathway
01:24Caspases
01:28Cells of the Innate Immune Response
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...
01:38Inflammation