Neutrophils and Lactoferrin
LF plays an important role in host defense, upon its release from the neutrophil (26). LF also enhances natural killer cell activity in immune defense (135) and can restrict the entry of the virus into host cells during infection. As part of the host's inflammatory response, leucocytes, including neutrophils, release LF from their granules, where it is normally stored. Activated neutrophils also release chromatin fibers, known as neutrophil extracellular traps (NETs), which trap and kill, amongst others, bacteria (1, 136). These NETs likewise modulate both acute and chronic inflammation (137, 138). NETs are also found in various autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus (139, 140). Interestingly, 106 human neutrophils can release 15 μg of LF (26). In addition to DNA and histones, NET fibers contain extranuclear proteins and proteins such as elastase, myeloperoxidase (MPO), and LF (141). LF may also serve as an intrinsic inhibitor of NETs release into the circulation, and may therefore be central in controlling NETs release (1). See Figure 3.
Figure 3  Bacterial binding to various receptors, e.g., Toll-like receptors 2 and 4 (TLR2 and 4), as well as complement receptors, leads to protein arginine deiminase 4 (PAD4) activation, followed by chromatin decondensation, hypercitrullination of histones 3 and 4 in the nucleus, and nuclear membrane disruption. Granules also release lactoferrin. Neutrophil Extracellular Traps (NETs) and their protein constituents (including lactoferrin) are released from the neutrophil. Adapted from Jorch and Kubes (142) and Law and Gray (143). Bacteria are expelled and trapped in the NETs. Diagram created with BioRender (https://biorender.com/).