Regulation of myeloid-cell activation

[Display omitted] •Myeloid-cell regulation optimizes innate/adaptive immunity and tissue health.•Competing positive and negative signaling biases and tunes myeloid activation.•Src-family kinase (e.g. Lyn) signaling is regulated by environment and cell type.•Dysregulated myeloid activation drives autoimmunity, cancer, and cytokine storm.•Defining context-specific myeloid regulatory mechanisms may yield novel therapies. Myeloid cells (macrophages, monocytes, dendritic cells, and granulocytes) survey the body for signs of infection and damage and regulate tissue homeostasis, organogenesis, and immunity. They express receptors that initiate the inflammatory response, send signals that alter the vascular and cytokine milieu, and oversee the recruitment, differentiation, and activation of other myeloid and adaptive immune cells. Their activation must therefore be tightly regulated, optimized for maximal innate-immune protection with a minimum of collateral tissue damage or disorganization. In this review we discuss what it means for myeloid cells to become activated, with emphasis on the receptors and signaling molecules important for the recognition of pathogen-associated and damage-associated molecular patterns. We also outline how these signals are regulated by the steric properties of proteins, by adhesive and cytoskeletal interactions, and by negative feedback to keep inflammation in check and support healthy tissue development and homeostasis. Throughout the text we highlight recent publications and reviews and direct readers therein for a comprehensive bibliography.