Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity.

Ryosuke Seki,Haruna Naito,Yoshinori Sugimine,Akira Ohta,Megumu K Saito,Akira Niwa,Tatsutoshi Nakahata,Xiaoping Bao

doi:10.1371/journal.pone.0237030

Abstract

Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC)-derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high-throughput screening (HTS) system to detect compounds that inhibit IL-1β secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA-approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL-1β inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells.

Highlights

One of the main cell types affected by immunological disorders are white blood cells, such as lymphocytes, monocytes, and neutrophils
We developed an high-throughput screening (HTS) system to identify compounds that regulate the activity of NLRP3 inflammasome using induced pluripotent stem cell (iPSC) generated from a neonatal onset multisystem inflammatory disease (NOMID) patient
We previously reported that macrophages derived from iPSCs carrying disease-associated mutations in the NLRP3 gene showed excessive secretion of IL-1β without secondary signals [30]

Summary

Introduction

One of the main cell types affected by immunological disorders are white blood cells, such as lymphocytes, monocytes, and neutrophils. Our understanding of the cellular pathophysiology of immunological disorders has greatly benefited from in vitro studies using patient-derived primary hematopoietic cells or in vivo animal models, these approaches have several limitations. Patient-derived hematopoietic cells cannot be obtained in sufficient quantities, and their in vitro phenotypes can be affected by the in vivo conditions of the patient, such as the cytokine milieu or the administration of therapeutic agents. While animal models have provided important insights into these disorders, species differences in the immunological. IPSC-derived monocytic cell lines serves a platform for drug screening

Methods

Results

Conclusion