Fig. 2

Response of host immune cells during different phases of biofilm formation. IAI can be divided into reversible and irreversible phases. This is closely related to the time interval of bacterial colonization on the implants. In the early stages of bacterial adhesion, innate immune cells can effectively kill bacteria by phagocytosis, oxidative bursts, production of antimicrobial peptides (AMPs), formation of neutrophil extracellular traps (NETs) and secretion of pro-inflammatory cytokines (such as IL-1β, IL-6 and TNF-α) and chemokines (such as MCP-1 and CXCL1). Because of the susceptibility of bacteria to clearance by host immune cells at this stage, it is considered a window for effective prevention of IAI. Biofilms mature gradually as bacteria accumulate and produce extracellular polymeric substances (EPSs, such as PIA and eDNA), which not only hinder the penetration and attack of antibiotics and immune cells but also skew the local immune response toward the anti-inflammatory type and suppress the host defense system. For instance, biofilms induce macrophage polarization from the classic M1 toward the M2 phenotype, which is characterized by the increased expression of anti-inflammatory cytokines (such as IL-4, IL-10, IL-12 and Arg-1) and attenuated antimicrobial peptide production. Simultaneously, they modulate the excessive expression of myeloid-derived suppressor cells (MDSCs, a population of immature myeloid cells mainly exerting strong immunosuppressive effects). The formation of mature biofilms marks the irreversible stage of infection. When bacteria within a mature biofilm reach a certain number, they will be dispersed and migrate to a new site to form new biofilms. Dispersal is facilitated by enzymatic degradation of surfactant molecules and EPSs and inhibition of biofilm matrix production. The quorum sensing system regulates the production of degrading enzymes in a density-dependent manner