NLRP6 Serves as a Negative Regulator of Neutrophil Recruitment and Function During Streptococcus pneumoniae Infection
Qi Tao1, Dongyi Xu1,2, Kaixiang Jia1
1Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing, China.
Insights
NOD-like receptor family pyrin domain containing 6 (NLRP6) negatively regulates host defense against Streptococcus pneumoniae. NLRP6 knockout mice show improved neutrophil function and reduced bacterial burden, suggesting therapeutic potential.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Streptococcus pneumoniae causes significant morbidity and mortality, particularly in vulnerable populations.
- NOD-like receptor family pyrin domain containing 6 (NLRP6) is implicated in innate immunity against pathogens.
- Previous research suggests NLRP6 negatively regulates host defense against S. pneumoniae, but mechanisms are unclear.
Purpose of the Study:
- To investigate the negative regulatory role of NLRP6 in host defense against S. pneumoniae infection.
- To elucidate the underlying mechanisms of NLRP6's detrimental effect on host immunity.
Main Methods:
- Utilized NLRP6 knockout (NLRP6-/-) and wild-type (WT) mice models.
- Assessed bacterial burden, tight junction protein expression (occludin), and transcriptome analysis.
- Measured chemokine expression (CXCL1, CXCL2), complement receptor expression (C3aR1), and P-selectin glycoprotein ligand-1 (PSGL-1).
- Evaluated neutrophil intracellular bactericidal activity and neutrophil extracellular trap (NET) formation.
Main Results:
- NLRP6-/- mice exhibited lower lung bacterial burdens and increased occludin expression post-infection.
- Transcriptome analysis revealed differential expression of leukocyte migration and recruitment genes.
- NLRP6-/- mice showed elevated CXCL1/CXCL2 and reduced C3aR1/PSGL-1 expression.
- NLRP6-/- neutrophils demonstrated enhanced intracellular killing and NET formation.
Conclusions:
- NLRP6 acts as a negative regulator of neutrophil recruitment and function during S. pneumoniae infection.
- Targeting NLRP6 may offer novel therapeutic strategies for invasive pneumococcal infections.
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.
