Abstract Tumor-associated macrophages (TAM) have served as a paradigm of cancer-related inflammation. Moreover, investigations on TAM have led to the dissection of macrophage plasticity and polarization and to the discovery and analysis of molecular pathways of innate immunity, in particular cytokines, chemokines and PTX3 as a prototypic fluid phase pattern recognition molecule. Mechanisms of negative regulation are complex and include decoy receptors, receptor antagonists, anti-inflammatory cytokines and the signalling regulator IL-1R8. In this review, topics and open issues in relation to regulation of innate immunity and inflammation are discussed: 1) how macrophage and neutrophil plasticity and polarization underlie diverse pathological conditions ranging from autoimmunity to cancer and may pave the way to innovative diagnostic and therapeutic approaches; 2) the key role of decoy receptors and negative regulators (e.g. IL-1R2, ACKR2, IL-1R8) in striking a balance between amplification of immunity and resolution versus uncontrolled inflammation and tissue damage; 3) role of humoral innate immunity, illustrated by PTX3, in resistance against selected microbes, regulation of inflammation and immunity and tissue repair, with implications for diagnostic and therapeutic translation. Highlights Macrophage plasticity and polarization is a fundamental mechanism involved in inflammation, autoimmunity and cancer. Decoy receptors are an evolutionary conserved mechanism to regulate the action of cytokines and chemokines. Negative regulators are key to balance amplification of immunity and uncontrolled inflammation and tissue damage. Negative regulators are essential for resolution of inflammation, whose failure determines immunopathology.
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