NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

Abstract

Schistosomiasis is a debilitating parasitic disease that affects more than 200 million people worldwide and causes approximately 280,000 deaths per year. Inside the definitive host, eggs released by Schistosoma mansoni lodge in the intestine and especially in the liver where they induce a granulomatous inflammatory process, which can lead to fibrosis. The molecular mechanisms initiating or promoting hepatic granuloma formation remain poorly understood. Inflammasome activation has been described as an important pathway to induce pathology mediated by NLRP3 receptor. Recently, other components of the inflammasome pathway, such as NLRP6, have been related to liver diseases and fibrotic processes. Nevertheless, the contribution of these components in schistosomiasis-associated pathology is still unknown. In the present study, using dendritic cells, we demonstrated that NLRP6 sensor is important for IL-1β production and caspase-1 activation in response to soluble egg antigens (SEA). Furthermore, the lack of NLRP6 has been shown to significantly reduce periovular inflammation, collagen deposition in hepatic granulomas and mRNA levels of α-SMA and IL-13. Livers of Nlrp6 −/− mice showed reduced levels of CXCL1/KC, CCL2, CCL3, IL-5, and IL-10 as well as Myeloperoxidase (MPO) and Eosinophilic Peroxidase (EPO) enzymatic activity. Consistently, the frequency of macrophage and neutrophil populations were lower in the liver of NLRP6 knockout mice, after 6 weeks of infection. Finally, it was further demonstrated that the onset of hepatic granuloma and collagen deposition were also compromised in Caspase-1 −/− , IL-1R −/− and Gsdmd −/− mice. Our findings suggest that the NLRP6 inflammasome is an important component for schistosomiasis-associated pathology.

The NLRP6 inflammasome

“…Taken together, a protective role of NLPR6 in the liver is suggested across different disease models. In contrast, parasitic‐induced liver fibrosis by Schistosoma mansoni infection in whole body of Nlrp6 ‐deficient mice is associated with a reduced macrophage and neutrophil infiltration, coupled with abrogated cytokine release (eg CCL2, CCL3, IL‐10 and IL‐5) and collagen deposition 58 . Cell‐specific depletion of Nlrp6 may clarify these apparent contradictory NLRP6‐driven innate immune responses noted in different liver disease models.…”

Neutrophils and schistosomiasis: a missing piece in pathology

“…Moreover, mice knockout for IL-1R presented lower granuloma size. 84 In turn, other studies on the subject, irrefutably report the inflammasome pathway, through NLRP3 and IL-1β production, impact granuloma formation. 85,86 Even though these latter findings demonstrated lower cell recruitment into the liver, they do not specifically point out which cell populations had their migration influenced by inflammasome pathway impairing.…”

Nod-like Receptors: Critical Intracellular Sensors for Host Protection and Cell Death in Microbial and Parasitic Infections

“…In parasitic infection, severe inflammation ascribed to soluble Egg Antigen (SEA) of Schistosoma mansoni (causative agent of gastrointestinal schistosomiasis) is crucially mediated by NLRP6 inflammasome activation, which intensifies chemokines production (CXCL1/KC, CCL2, CCL3, IL-5 and IL-10) and immune cell recruitment into the liver. Caspase 1 and IL-1β in the liver dendritic cells are critical for GSDMD-dependent hepatic granuloma, resulting in periovular inflammation and collagen deposition [ 170 ]. In contrast, the release of IL-18 via enterocyte NLRP6 inflammasome activation is necessary for parasite clearance in intestinal infection caused by Cryptosporidium tyzzeri [ 171 ].…”