Sex-dependent differential activation of NLRP3 and AIM2 inflammasomes in SLE macrophages

Abstract

Objective: SLE is more prevalent in females, but may cause more severe organ damage in males. The underlying mechanism is incompletely understood. Since macrophage plays a key role in SLE pathogenesis, the present work aimed to investigate whether inflammasomes in male and female SLE macrophages are differentially activated.

Methods: Macrophages were derived from peripheral blood mononuclear cells of SLE patients and healthy controls. Adenosine triphosphate-stimulated IL-1β in lipopolysaccharide-primed macrophages was measured via ELISA. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 (AIM2) mRNA expression in macrophages were determined by RT-PCR. We further genotyped SLE patients for single nucleotide polymorphisms of NLRP3 and an NLRP3 regulator caspase recruitment domain family, member 8 (CARD8).

Results: ATP-induced IL-1β production was increased in macrophages of both male and female SLE patients. Overexpression of NLRP3 mRNA was detected in unstimulated female SLE macrophages, while CARD8 variant allele is associated with SLE susceptibility in males. Moreover, AIM2 mRNA expression in unstimulated macrophages was found to be elevated in male SLE patients, but decreased in female SLE patients. However, the autoantibody titre of dsDNA, an AIM2 ligand, is associated with SLE disease severity only in female patients.

Conclusion: Our study shows for the first time that the NLRP3 inflammasome is hyperactivated in macrophages of both male and female SLE patients. The mechanisms underlying NLRP3 hyperactivation might be different between the sexes. Furthermore, the AIM2 inflammasome might also contribute sex-differentially to SLE pathogenesis and severity.

Keywords: inflammasome; macrophage; sex; systemic lupus erythematosus.