NF-κB activation in cardiac fibroblasts results in the recruitment of inflammatory Ly6Chi monocytes in pressure-overloaded hearts

TY - JOUR

T1 - NF-κB activation in cardiac fibroblasts results in the recruitment of inflammatory Ly6Chi monocytes in pressure-overloaded hearts

AU - Abe, Hajime

AU - Tanada, Yohei

AU - Omiya, Shigemiki

AU - Podaru, Mihai-Nicolae

AU - Murakawa, Tomokazu

AU - Shah, Ajay

AU - Ito, Jumpei

AU - Ono, Masahiro

AU - Conway, Simon J.

AU - Otsu, Kinya

PY - 2021/10/12

Y1 - 2021/10/12

N2 - Heart failure is a major public health problem and inflammation is involved in its pathogenesis. Inflammatory Ly6C 37 hi monocytes accumulate in mouse hearts after pressure overload and are detrimental to the heart; however, the types of cells that drive inflammatory cell recruitment remains uncertain. Here, we showed that a distinct subset of mouse cardiac fibroblasts became activated by pressure overload and recruited Ly6C 40 hi monocytes to the heart. Single-cell sequencing analysis revealed that a subset of cardiac fibroblasts highly expressed genes transcriptionally activated by the transcription factor NF-κB, as well as CC motif chemokine ligand 2 (Ccl2) mRNA, which encodes a major factor in Ly6Chi monocyte recruitment. The deletion of the NF-κB activator IKKβ in activated cardiac fibroblasts attenuated Ly6C 45 hi monocyte recruitment and preserved cardiac function in mice subjected to pressure overload. Pseudotime analysis indicated two single-branch trajectories from quiescent fibroblasts into inflammatory fibroblasts and myofibroblasts. Our results provide insight into the mechanisms underlying cardiac inflammation and fibroblast mediated inflammatory responses that could be therapeutically targeted to treat heart failure

AB - Heart failure is a major public health problem and inflammation is involved in its pathogenesis. Inflammatory Ly6C 37 hi monocytes accumulate in mouse hearts after pressure overload and are detrimental to the heart; however, the types of cells that drive inflammatory cell recruitment remains uncertain. Here, we showed that a distinct subset of mouse cardiac fibroblasts became activated by pressure overload and recruited Ly6C 40 hi monocytes to the heart. Single-cell sequencing analysis revealed that a subset of cardiac fibroblasts highly expressed genes transcriptionally activated by the transcription factor NF-κB, as well as CC motif chemokine ligand 2 (Ccl2) mRNA, which encodes a major factor in Ly6Chi monocyte recruitment. The deletion of the NF-κB activator IKKβ in activated cardiac fibroblasts attenuated Ly6C 45 hi monocyte recruitment and preserved cardiac function in mice subjected to pressure overload. Pseudotime analysis indicated two single-branch trajectories from quiescent fibroblasts into inflammatory fibroblasts and myofibroblasts. Our results provide insight into the mechanisms underlying cardiac inflammation and fibroblast mediated inflammatory responses that could be therapeutically targeted to treat heart failure

UR - http://www.scopus.com/inward/record.url?scp=85118380754&partnerID=8YFLogxK

U2 - 10.1126/scisignal.abe4932

DO - 10.1126/scisignal.abe4932

M3 - Article

SN - 1945-0877

VL - 14

SP - eabe4932

JO - Science Signaling

JF - Science Signaling

IS - 704

ER -