NLRP6 Serves as a Negative Regulator of Neutrophil Recruitment and Function During Streptococcus pneumoniae Infection

Abstract

Streptococcus pneumoniae is an invasive pathogen with high morbidity and mortality in the immunocompromised children and elderly. NOD-like receptor family pyrin domain containing 6 (NLRP6) plays an important role in the host innate immune response against pathogen infections. Our previous studies have shown that NLRP6 plays a negative regulatory role in host defense against S. pneumoniae, but the underlying mechanism is still unclear. The further negative regulatory role of NLRP6 in the host was investigated in this study. Our results showed that NLRP6−/− mice in the lung had lower bacterial burdens after S. pneumoniae infection and expressed higher level of tight junction (TJ) protein occludin compared to WT mice, indicating the detrimental role of NLRP6 in the host defense against S. pneumoniae infection. Transcriptome analysis showed that genes related to leukocytes migration and recruitment were differentially expressed between wild-type (WT) and NLRP6 knockout (NLRP6−/−) mice during S. pneumoniae infection. Also, NLRP6−/− mice showed higher expression of chemokines including C-X-C motif chemokine ligand 1 (CXCL1) and 2 (CXCL2) and lower gene expression of complement C3a receptor 1 (C3aR1) and P-selectin glycoprotein ligand-1 (PSGL-1) which are the factors that inhibit the recruitment of neutrophils. Furthermore, NLRP6−/− neutrophils showed increased intracellular bactericidal ability and the formation of neutrophil extracellular traps (NETs) during S. pneumoniae infection. Taken together, our study suggests that NLRP6 is a negative regulator of neutrophil recruitment and function during S. pneumoniae infection. Our study provides a new insight to develop novel strategies to treat invasive pneumococcal infection.

Activation of inflammasomes and mechanisms for intracellular recognition of Listeria monocytogenes

“…This response is facilitated by Listeria virulence factors such as LLO 80,111 . Similar phenomena have been reported with other pathogens, such as Staphylococcus aureus , Bacillus cereus , Streptococcus pneumoniae , Mycobacterium tuberculosis , and COVID‐19 73–77,112–114 . The inflammasome regulates the production of pro‐inflammatory cytokines IL‐1β and IL‐18 through caspase‐1 activation.…”

“…This highlights the importance of Listeria monocytogenes possessing ligands that can activate the inflammasome. Similar observations have been reported for other Gram‐positive bacteria, such as Staphylococcus aureus , Bacillus cereus , and Streptococcus pneumoniae , where inflammasome responses contribute to the worsening of host pathology 73–77 . Understanding the mechanisms of inflammasome activation by pathogenic bacteria is crucial for comprehending infectious diseases.…”

“…80,111 Similar phenomena have been reported with other pathogens, such as Staphylococcus aureus, Bacillus cereus, Streptococcus pneumoniae, Mycobacterium tuberculosis, and COVID-19. [73][74][75][76][77][112][113][114] The inflammasome regulates the production of pro-inflammatory cytokines IL-1β and IL-18 through caspase-1 activation. These cytokines may be implicated in a cytokine storm in patients.…”

“…Similar observations have been reported for other Gram-positive bacteria, such as Staphylococcus aureus, Bacillus cereus, and Streptococcus pneumoniae, where inflammasome responses contribute to the worsening of host pathology. [73][74][75][76][77] Understanding the mechanisms of inflammasome activation by pathogenic bacteria is crucial for comprehending infectious diseases. In this review, we provide an overview of the reported factors responsible for inflammasome activation in Listeria monocytogenes and the mechanisms of their activation (Figure 1).…”

Identification of Pyroptosis-Related Genes Regulating the Progression of Chronic Rhinosinusitis with Nasal Polyps

“…Tissue homeostasis is strictly regulated by the NLRP6 inflammasome. Hence, abnormal activation of the NLRP6 inflammasome can result in multiple diseases, namely, Streptococcus pneumoniae infections [42][43][44]. The three aforementioned genes potentially utilize multiple pathways to modulate innate immune response to various stimuli, thereby initiating non-programmed cellular death and further exacerbating the inflammatory process in CRSwNP via activation of various modes of pyroptosis.…”