KLF2 in Myeloid Lineage Cells Regulates the Innate Immune Response during Skeletal Muscle Injury and Regeneration

Palanikumar Manoharan; Taejeong Song; Tatiana L Radzyukevich; Sakthivel Sadayappan; Jerry B Lingrel; Judith A Heiny

doi:10.1016/j.isci.2019.07.009

KLF2 in Myeloid Lineage Cells Regulates the Innate Immune Response during Skeletal Muscle Injury and Regeneration

iScience. 2019 Jul 26:17:334-346. doi: 10.1016/j.isci.2019.07.009. Epub 2019 Jul 8.

Authors

Palanikumar Manoharan¹, Taejeong Song², Tatiana L Radzyukevich³, Sakthivel Sadayappan², Jerry B Lingrel⁴, Judith A Heiny⁵

Affiliations

¹ Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA. Electronic address: manohapr@ucmail.uc.edu.
² Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
³ Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
⁴ Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
⁵ Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA. Electronic address: heinyja@ucmail.uc.edu.

Abstract

Skeletal muscle repair and regeneration after injury requires coordinated interactions between the innate immune system and the injured muscle. Myeloid cells predominate in these interactions. This study examined the role of KLF2, a zinc-finger transcription factor that regulates immune cell activation, in specifying myeloid cell functions during muscle regeneration. Loss of KLF2 in myeloid lineage cells (myeKlf2^-/- mice) dramatically enhanced the initial inflammatory response to acute muscle injury (cardiotoxin). Injured muscles showed dramatically elevated expression of inflammatory mediators and greater numbers of infiltrating, pro-inflammatory monocytes that matured earlier into activated macrophages. Notably, the inflammatory phase resolved earlier and regeneration progressed to myogenesis, marked by elevated expression of factors that promote the formation of new fibers from satellite cells. Regeneration was completed earlier, with phenotypically normal adult fibers integrated into the muscle syncytium. These findings identify myeloid KLF2 as a key regulator of myeloid cell functions in adult skeletal muscle regeneration.

Keywords: Immune Response; Immunology; Molecular Physiology; Physiology.

Grants and funding

R01 AR063710/AR/NIAMS NIH HHS/United States