IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge

Abstract

<p id="P1">In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here we show that IL-4 differentiated M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptor from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure and led to insulin-resistance in mice fed high fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knock out (MIKO) revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth <i>Nippostrongylus brasiliensis</i> displayed delayed resolution from infection with normal insulin-sensitivity. Surprisingly, cold –challenge did not trigger overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage activation phenotype. </p><p id="P2">Endocrine IGF1 plays pleiotropic functions and provides signals to macrophages to sustain tissue development and homeostasis. In this work Spadaro et al. show that M2-like macrophages are an important source of IGF1 itself and that the myeloid-derived IGF1R signaling regulates immune-metabolism. Host adaptation to high-fat diet induced obesity and helminth clearance requires myeloid IGF1R but not the response to cold-stress. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/6dd40acd-698c-470c-a286-e97bc0be0e2a/PubMedCentral/image/nihms862819u1.jpg"/> </div> </p>