Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia

Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer. [Display omitted] •Cancer cachexia exhibits muscle inflammation, regulated by NF-κB from multiple cell types•Muscle inflammation in cancer cachexia is mediated by myeloid cells, mostly macrophages•Macrophages in cachectic muscle derive from infiltrating monocytes and resident cells•Heterogeneous populations of macrophages exhibit both pro- and anti-atrophy activities We demonstrate that NF-κB functions in multiple cells in skeletal muscle to expand macrophages during cancer cachexia, deriving from infiltrating monocytes and resident cells. Macrophages contribute to muscle wasting and preservation of myofibers. They also crosstalk with muscle stem cells, myofibers, and fibro-adipogenic progenitors to sustain NF-κB activity and inflammation.