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bioRxiv · 10.1101/312868

Krüppel like factor 2 - deficient myeloid cells promote skeletal muscle regeneration after injury

Manoharan, P.·Song, T.·Radzyukevich, T. L.·Sadayappan, S.·Lingrel, J. B.·Heiny, J. A.
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Abstract

Regeneration of adult skeletal muscle after injury is coordinated by complex interactions between the injured muscle and the innate immune system. Myeloid lineage cells predominate in this process. This study examined the role of Kruppel - like factor 2 (KLF2), a zinc-finger transcription factor that regulates myeloid cell activation state, in muscle regeneration. Gastrocnemius muscles of wild-type and myeKlf2-/- mice, which lack KLF2 in all myeloid cells, were subjected to cardiotoxin injury and followed for 21 days. Injured muscles of myeKlf2-/- contained more infiltrating, inflammatory Ly6C+ monocytes, with elevated expression of inflammatory mediators. Infiltrating monocytes matured earlier into pro-inflammatory macrophages with phenotype Ly6C+, CD11b+, F4/80+. Inflammation resolved earlier and progressed to myogenesis, marked by an earlier decline of Ly6C+ macrophages and their replacement with anti-inflammatory Ly6C- populations, in association with elevated expression of factors that resolve inflammation and promote myogenesis. Overall, regeneration was completed earlier. These findings identify myeloid KLF2 as a central regulator of the innate immune response to acute skeletal muscle injury. Manipulating myeloid KLF2 levels may be a useful strategy for accelerating regeneration.\n\nO_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY SynopsisThe zinc-finger transcription factor, KLF2, is a central regulator of the innate immune response to skeletal muscle injury. Targeted deletion of KLF2 in myeloid lineage cells of mice (myeKlf2-/-) enhances the immune response and, notably, accelerates muscle repair. O_LIInjured muscles of myeKlf2-/- mice recruit greater numbers of Ly6C+ (inflammatory) monocytes from the circulation.\nC_LIO_LIThese mature in situ into pro-inflammatory macrophages which phagocytose necrotic tissue and prepare the environment for muscle regeneration.\nC_LIO_LISubsequently, Ly6C+ macrophages decline and are replaced by anti-inflammatory (Ly6C-) macrophages that promote myogenesis of new fibers.\nC_LIO_LIInjured muscles of myeKlf2-/- mice complete regeneration earlier, with phenotypically adult fibers.\nC_LI\n\nC_FIG_DISPLAY

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Manoharan, P., Song, T., Radzyukevich, T. L., Sadayappan, S., Lingrel, J. B., Heiny, J. A.. 2018-05-02. Krüppel like factor 2 - deficient myeloid cells promote skeletal muscle regeneration after injury. https://doi.org/10.1101/312868

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