Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment.

Tyler K Ulland,Polly J Ferguson,Mary E Wilson,Mohammed Bourdi,Gwendolyn M Clay,Jeffrey J Sadler,Nidhi Jain,Kathleen A M Mills,Kevin L Legge,A Paige Davis Volk,Eric I Elliott,Lokesh Gakhar,Ann M Janowski,Suzanne L Cassel,Kai Wang,Fayyaz S Sutterwala,Emma E Hornick

doi:10.1038/ncomms13180

Abstract

The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases. Here we show that C57BL/6J mice have a defect in neutrophil recruitment to a range of inflammatory stimuli compared with the related C57BL/6N substrain. This immune perturbation is associated with a missense mutation in Nlrp12 in C57BL/6J mice. Both C57BL/6J and NLRP12-deficient mice have increased susceptibility to bacterial infection that correlates with defective neutrophil migration. C57BL/6J and NLRP12-deficient macrophages have impaired CXCL1 production and the neutrophil defect observed in C57BL/6J and NLRP12-deficient mice is rescued by restoration of macrophage NLRP12. These results demonstrate that C57BL/6J mice have a functional defect in NLRP12 and that macrophages require NLRP12 expression for effective recruitment of neutrophils to inflammatory sites.

Highlights

The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases
To define at what point neutrophil migration was disrupted in Nlrp[12] À / À mice, we evaluated the in vivo mobilization of inflammatory cells in response to infection with F. tularensis live vaccine strain (LVS)
Our work demonstrates differences in inflammatory responses between C57BL/6N and C57BL/6J mouse substrains with C57BL/6J mice having a failure of neutrophil recruitment to a wide variety of inflammatory stimuli compared with the related C57BL/6N substrain

Summary

Introduction

The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases. We show that C57BL/6J mice have a defect in neutrophil recruitment to a range of inflammatory stimuli compared with the related C57BL/6N substrain This immune perturbation is associated with a missense mutation in Nlrp[12] in C57BL/6J mice. We demonstrate that C57BL/6J mice have a defect in recruitment of neutrophils to inflammatory sites in vivo. This immune perturbation in C57BL/6J mice is associated with a missense mutation within the leucine-rich repeat domain of Nlrp[12] resulting in an arginine to lysine change (R1034K). Our findings demonstrate that NLRP12 controls neutrophil migration to inflammatory sites and that a missense mutation in Nlrp[12] in C57BL/6J mice renders these mice with a functional NLRP12 deficit

Methods

Results

Conclusion