Emerging Role of Immunosuppression in Diseases Induced by Micro- and Nano-Particles: Time to Revisit the Exclusive Inflammatory Scenario

Fibrosis, cancer, and autoimmunity developing upon particle exposure have been exclusively linked with uncontrolled inflammatory processes. The critical role of inflammation is now challenged by several contradictory observations indicating that the emergence of these chronic disorders may result from non-inflammatory events. A growing number of studies reveals that micro- and nano-particles can cause exaggerated and persistent immunosuppression characterized by the release of potent anti-inflammatory cytokines (IL-10 and TGF-β), and the recruitment of major regulatory immune cells (M2 macrophages, T and B regs, and MDSC). This persistent immunosuppressive environment is initially established to limit early inflammation but contributes later to fibrosis, cancer, and infection. Immunosuppression promotes fibroblast proliferation and matrix element synthesis and subverts innate and adaptive immune surveillance against tumor cells and microorganisms. This review details the contribution of immunosuppressive cells and their derived immunoregulatory mediators and delineates the mutual role of inflammatory vs. immunosuppressive mechanisms in the pathogenesis of chronic diseases induced by particles. The consideration of these new results explains how particle-related diseases can develop independently of chronic inflammation, enriches current bioassays predicting particle toxicity and suggests new clinical strategies for treating patients affected by particle-associated diseases.