Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11c^bright/CD62L^dim/CD11b^bright/CD16^bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide from the neutrophils into the immunological synapse between the neutrophils and T cells mediated the suppression of T cell proliferation and required neutrophil expression of the integrin Mac-1 (αMβ2). Our data demonstrate that suppression of T cell function can be accomplished by a subset of human neutrophils that can be systemically induced in response to acute inflammation. Identification of the pivotal role of neutrophil Mac-1 and ROS in this process provides a potential target for modulating immune responses in humans.

Systemic inflammation results in release of refractory neutrophils which can cause susceptibility to infections and activates differentiated neutrophils, which can mediate tissue damage. Neutrophils play an important role in host defense. However, deregulation of neutrophils contributes to tissue damage in severe systemic inflammation. In contrast to complications mediated by an overactive neutrophil compartment, severe systemic inflammation is a risk factor for development of immune suppression and as a result, infectious complications. The role of neutrophils in this clinical paradox is poorly understood, and in this study, we tested whether this paradox could be explained by distinct neutrophil subsets and their functionality. We studied the circulating neutrophil compartment immediately after induction of systemic inflammation by administering 2 ng/kg Escherichia coli LPS i.v. to healthy volunteers. Neutrophils were phenotyped by expression of membrane receptors visualized by flow cytometry, capacity to interact with fluorescently labeled microbes, and activation of the NADPH-oxidase by oxidation of Amplex Red and dihydrorhodamine. After induction of systemic inflammation, expression of membrane receptors on neutrophils, such as CXCR1 and -2 (IL-8Rs), C5aR, FcγRII, and TLR4, was decreased. Neutrophils were also refractory to fMLF-induced up-regulation of membrane receptors, and suppression of antimicrobial function was shown by decreased interaction with Staphylococcus epidermis. Simultaneously, activation of circulating neutrophils was demonstrated by a threefold increase in release of ROS. The paradoxical phenotype can be explained by the selective priming of the respiratory burst. In contrast, newly released, CD16dim banded neutrophils display decreased antimicrobial function. We conclude that systemic inflammation leads to a functionally heterogeneous neutrophil compartment, in which newly released refractory neutrophils can cause susceptibility to infections, and activated, differentiated neutrophils can mediate tissue damage.

Background: Although the phrase “time is fascia” is well acknowledged in the case of necrotizing soft tissue infections (NSTIs), solid evidence is lacking. The aim of this study is to review the current literature concerning the timing of surgery in relation to mortality and amputation in patients with NSTIs. Methods: A systematic search in PubMed/MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Controlled Register of Trials (CENTRAL) was performed. The primary outcomes were mortality and amputation. These outcomes were related to the following time-related variables: (1) time from onset symptoms to presentation; (2) time from onset symptoms to surgery; (3) time from presentation to surgery; (4) duration of the initial surgical procedure. For the meta-analysis, the effects were estimated using random-effects meta-analysis models. Result: A total of 109 studies, with combined 6051 NSTI patients, were included. Of these 6051 NSTI patients, 1277 patients died (21.1%). A total of 33 studies, with combined 2123 NSTI patients, were included for quantitative analysis. Mortality was significantly lower for patients with surgery within 6 h after presentation compared to when treatment was delayed more than 6 h (OR 0.43; 95% CI 0.26–0.70; 10 studies included). Surgical treatment within 6 h resulted in a 19% mortality rate compared to 32% when surgical treatment was delayed over 6 h. Also, surgery within 12 h reduced the mortality compared to surgery after 12 h from presentation (OR 0.41; 95% CI 0.27–0.61; 16 studies included). Patient delay (time from onset of symptoms to presentation or surgery) did not significantly affect the mortality in this study. None of the time-related variables assessed significantly reduced the amputation rate. Three studies reported on the duration of the first surgery. They reported a mean operating time of 78, 81, and 102 min with associated mortality rates of 4, 11.4, and 60%, respectively. Conclusion: Average mortality rates reported remained constant (around 20%) over the past 20 years. Early surgical debridement lowers the mortality rate for NSTI with almost 50%. Thus, a sense of urgency is essential in the treatment of NSTI.

Apart from their pivotal role in the host defense against pathogens, leukocytes are also essential for bone repair, as fracture healing is initiated and directed by a physiological inflammatory response. Leukocytes infiltrate the fracture hematoma and produce several growth and differentiation factors that regulate essential downstream processes of fracture healing. Systemic inflammation alters the numbers and properties of circulating leukocytes, and we hypothesize that these changes are maintained in tissue leukocytes and will lead to impairment of fracture healing after major trauma. The underlying mechanisms will be discussed in this review.

The role of inflammatory cells in bone regeneration remains unclear. We hypothesize that leukocytes contribute to fracture healing by rapidly synthesizing an "emergency extracellular matrix (ECM)" before stromal cells infiltrate the fracture hematoma (FH) and synthesize the eventual collagenous bone tissue. 53 human FHs were isolated at different time points after injury, ranging from day 0 until day 23 after trauma and stained using (immuno)histochemistry. FHs isolated within 48 h after injury contained fibronectin(+) ECM, which increased over time. Neutrophils within the early FHs stained positive for cellular fibronectin and neutrophil derived particles were visible within the fibronectin(+) ECM. Stromal cells appeared at day 5 after injury or later and collagen type I birefringent fibrils could be identified during the second week after injury. Our study suggests that neutrophils contribute to bone regeneration by synthesizing an "emergency ECM" before stromal cells infiltrate the FH and synthesize the eventual bone tissue.