Klf2 in Myeloid Lineage Cells Regulates the Innate Immune Response During Skeletal Muscle Injury and Regeneration

In response to skeletal muscle injury, myeloid lineage cells mediate a specific immune response that is essential for proper repair and regeneration. The zinc-finger transcription factor, Kruppel – like factor 2 (KLF2), is a central regulator of myeloid cell fates. This study examines the role of myeloid KLF2 in skeletal muscle regeneration after cardiotoxin (CTX) injury. Injured muscles of mice which lack KLF2 in myeloid lineage cells (myeKlf2-/-) show a markedly enhanced inflammatory response, greater numbers of infiltrating, inflammatory Ly6C+ monocytes, and increased expression of inflammatory mediators. Intramuscular Ly6C+ monocytes mature earlier into macrophages with phenotype Ly6C+, CD11b+, F4/80+ and this population is expanded in myeKlf2-/-. The critical transition from inflammation to myogenesis, evident in expanded populations of anti-inflammatory Ly6C- macrophages and elevated expression of myokines and myogenic regulatory factors, occurs earlier in myeKlf2-/-. These molecular and cellular markers coincide temporally with the expected histological indices of inflammation and necrosis, appearance of new myofibers with central nuclei and eMHC expression, and completion of regeneration with phenotypically adult myofibers. These findings underscore the importance of the innate immune response to muscle injury and identify myeloid KLF2 as a central regulator of myeloid cell functions in skeletal muscle repair and regeneration.