The liver is a key, frontline immune tissue. Ideally positioned to detect pathogens entering the body via the gut, the liver appears designed to detect, capture, and clear bacteria, viruses, and macromolecules. Containing the largest collection of phagocytic cells in the body, this organ is an important barrier between us and the outside world. Importantly, as portal blood also transports a large number of foreign but harmless molecules (e.g., food antigens), the liver's default immune status is anti-inflammatory or immunotolerant; however, under appropriate conditions, the liver is able to mount a rapid and robust immune response. This balance between immunity and tolerance is essential to liver function. Excessive inflammation in the absence of infection leads to sterile liver injury, tissue damage, and remodeling; insufficient immunity allows for chronic infection and cancer. Dynamic interactions between the numerous populations of immune cells in the liver are key to maintaining this balance and overall tissue health.

Monocytes are recruited from the blood to sites of inflammation, where they contribute to wound healing and tissue repair. There are at least two subsets of monocytes: classical or proinflammatory (CCR2hiCX3CR1low) and nonclassical, patrolling, or alternative (CCR2lowCX3CR1hi) monocytes. Using spinning-disk confocal intravital microscopy and mice with fluorescent reporters for each of these subsets, we were able to track the dynamic spectrum of monocytes that enter a site of sterile hepatic injury in vivo. We observed that the CCR2hiCX3CR1low monocytes were recruited early and persisted for at least 48 h, forming a ringlike structure around the injured area. These monocytes transitioned, in situ, from CCR2hiCx3CR1low to CX3CR1hiCCR2low within the ringlike structure and then entered the injury site. This phenotypic conversion was essential for optimal repair. These results demonstrate a local, cytokine driven reprogramming of classic, proinflammatory monocytes into nonclassical or alternative monocytes to facilitate proper wound-healing.

Well established for their central role in hemostasis, platelets have increasingly been appreciated as immune cells in recent years. This emerging role should not come as a surprise as the central immune cells of invertebrates, hemocytes, are able to phagocytose, secrete soluble mediators and promote coagulation of hemolymph, blurring the line between immunity and hemostasis. The undeniable evolutionary link between coagulation and immunity becomes even clearer as the role of platelets in inflammation is better understood. Platelets exert a range of immune-related functions, many of which involve an intimate interplay with leukocytes. Platelets promote leukocyte recruitment via endothelial activation and can serve as “landing pads” for leukocytes, facilitating cellular adhesion in vascular beds devoid of classic adhesion molecules. Moreover, platelets enhance leukocyte function both through direct interactions and through release of soluble mediators. Among neutrophil-platelets interactions, the modulation of neutrophil extracellular traps (NETs) is of great interest. Platelets have been shown to induce NET formation; and, in turn, NET components further regulate platelet and neutrophil function. While NETs have been shown to ensnare and kill pathogens, they also initiate coagulation via thrombin activation. In fact, increased NET formation has been associated with hypercoagulability in septic patients as well as in chronic vascular disorders. This review will delve into current knowledge of platelet-neutrophil interactions, with a focus on NET-driven coagulation, in the context of infectious diseases. A better understanding of these mechanisms will shed a light on the therapeutic potential of uncoupling immunity and coagulation through targeting of NETs.