Neutrophils in Health and Disease: From Receptor Sensing to Inflammasome Activation

Abstract

Neutrophils-polymorphonuclear cells (PMNs) are the cells of the initial immune response and make up the majority of leukocytes in the peripheral blood. After activation, these cells modify their functional status to meet the needs at the site of action or according to the agent causing injury. They receive signals from their surroundings and "plan" the course of the response in both temporal and spatial contexts. PMNs dispose of intracellular signaling pathways that allow them to perform a wide range of functions associated with the development of inflammatory processes. In addition to these cells, some protein complexes, known as inflammasomes, also have a special role in the development and maintenance of inflammation. These complexes participate in the proteolytic activation of key pro-inflammatory cytokines, such as IL-1β and IL-18. In recent years, there has been significant progress in the understanding of the structure and molecular mechanisms behind the activation of inflammasomes and their participation in the pathogenesis of numerous diseases. The available reports focus primarily on macrophages and dendritic cells. According to the literature, the activation of inflammasomes in neutrophils and the associated death type-pyroptosis-is regulated in a different manner than in other cells. The present work is a review of the latest reports concerning the course of inflammasome activation and inflammatory cytokine secretion in response to pathogens in neutrophils, as well as the role of these mechanisms in the pathogenesis of selected diseases.

Keywords: CAPS; COVID-19; cardiovascular disease; inflammasome; neutrophil; pyroptosis.

Figure 1

Formation of NLRP3 inflammasome and its activation through the canonical pathway. Abbreviations: PAMPs—pathogen-associated molecular patterns; DAMPs—damage-associated molecular patterns, MSU—crystals of monosodium urate; TLR—toll-like receptors; NF-kB—nuclear factor kappa-light-chain-enhancer of activated B cells; PTMs—post-translational modifications; ROS—reactive oxygen species; NLRP3—NLR family pyrin domain containing 3; ASC—apoptosis-associated speck-like protein containing a CARD; GSDM- gasdermin D; GSDMD-N—N-end fragment of gasdermin D. Signal 1 causes priming through the activation of NF-κB [16]. The action of this nuclear factor in the cell nucleus results in increased transcription of pro-IL-1β and NLRP3 genes and a series of posttranslational modifications, including phosphorylation, acetylation, and ubiquitination, enabling the NLRP3 protein to assume the appropriate conformation [25,26,27]. Signal 2, which is triggered by numerous extracellular stimuli, including danger-associated molecular patterns, pathogen-associated molecular patterns, or uric acid crystals, leads to the binding of NLRP3, ASC, and pro-caspase-1. Other intracellular signals may also contribute to the activation of inflammasomes, through the action of signal 2, lysosome burst, release of reactive oxygen species, or mitochondrial damage. In the next stage, pro-caspase-1 bound in the inflammasome complex undergoes autoproteolytic activation. Caspase-1 induces the proteolytic activation of pro-IL-1β to its active form and cleaves the N-end fragment of gasdermin D, which accumulates in the cell membrane, creating pores and enabling the release of IL-1β to the extracellular environment [19,28].

Figure 2

Non-canonical activation of NLRP3 inflammasomes. Abbreviations: LPS—lipopolysaccharide; NLRP3—NLR family pyrin domain containing 3; ASC—apoptosis-associated speck-like protein containing a CARD; GSDMD—gasdermin D; GSDMD-N—N-end fragment of gasdermin D. The non-canonical inflammasome pathway is activated by intracellular (e.g., in Escherichia coli infections) or extracellular (circulating) LPS. LPS has the ability to induce direct proteolytic activation of procaspase-4 and procaspase-5. Activation of inflammasome occurs due to the efflux of K⁺ ions from the cell or the cleavage of gasdermin D through the effect of active caspase-4 and caspase-5 [30,31].

Figure 3

The mechanism of immunothrombosis and inflammation mediated by neutrophils in the blood vessel of the heart.