Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction

Mieke C Louwe; Maria B Olsen; Ole J Kaasbøll; Kuan Yang; Linn E Fosshaug; Katrine Alfsnes; Jonas D S Øgaard; Azita Rashidi; Vidar M Skulberg; Mingyi Yang; Davi de Miranda Fonseca; Animesh Sharma; Jan Magnus Aronsen; Elisabeth Schrumpf; Muhammad Shakil Ahmed; Christen Peder Dahl; Tuula A Nyman; Thor Ueland; Espen Melum; Bente E Halvorsen; Magnar Bjørås; Håvard Attramadal; Ivar Sjaastad; Pål Aukrust; Arne Yndestad

doi:10.1016/j.jacbts.2020.09.013

Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction

JACC Basic Transl Sci. 2020 Dec 9;5(12):1210-1224. doi: 10.1016/j.jacbts.2020.09.013. eCollection 2020 Dec.

Authors

Mieke C Louwe¹, Maria B Olsen¹, Ole J Kaasbøll², Kuan Yang¹, Linn E Fosshaug^{1

3}, Katrine Alfsnes¹, Jonas D S Øgaard¹, Azita Rashidi¹, Vidar M Skulberg⁴, Mingyi Yang⁵, Davi de Miranda Fonseca⁶, Animesh Sharma⁶, Jan Magnus Aronsen^{4

7}, Elisabeth Schrumpf^{1

3

8}, Muhammad Shakil Ahmed², Christen Peder Dahl¹, Tuula A Nyman⁹, Thor Ueland^{1

3}, Espen Melum^{1

3

8

10}, Bente E Halvorsen^{1

3}, Magnar Bjørås^{3

5

11}, Håvard Attramadal^{2

3}, Ivar Sjaastad^{3

4}, Pål Aukrust^{1

3

12}, Arne Yndestad³

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
² Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
³ Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway.
⁵ Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁶ PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ Bjørknes College, Oslo, Norway.
⁸ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁹ Department of Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet Oslo, Oslo, Norway.
¹⁰ Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
¹¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹² Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Abstract

An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3 ^-/- mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1β and -18) in MI patients.

Keywords: ASC, apoptosis-associated speck like protein; CMR, cardiac magnetic resonance; ECM, extracellular matrix; HF, heart failure; I/R, ischemia/reperfusion; IL, interleukin; LV, left ventricle/ventricular; MI, myocardial infarction; NLRP3; NLRP3, NLR family, pyrin domain containing protein 3; WT, wild-type; cardiac remodeling; hematopoietic cells; innate immunity; macrophages; myocardial infarction.