Stem cells reside in a specialized regulatory microenvironment or niche1,2, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity1-3. The niche may also protect stem cells from environmental insults3 including cytotoxic chemotherapy and perhaps pathogenic immunity4. The testis, hair follicle, and placenta are all sites of residence for stem cells and are immune suppressive environments, called immune privileged (IP) sites, where multiple mechanisms conspire to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression (IS)4. We sought to determine if somatic stem cell niches more broadly are IP sites by examining the hematopoietic stem/progenitor cell (HSPC) niche1,2,5-7 in the bone marrow (BM), a site where immune reactivity exists8,9. We observed persistence of allo-HSPCs in non-irradiated recipients for 30 days without IS with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T cells (Tregs). High resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with Tregs that accumulated on the endosteal surface in the calvarial and trabecular BM. Tregs appear to participate in creating a localized zone where HSPCs reside and where Tregs are necessary for allo-HSPC persistence. In addition to processes supporting stem cell function, the niche will provide a relative sanctuary from immune attack.

IFN-b is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-b for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-b 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-a and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-a or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-b reversed the TNF-a/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-b improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

A NNUALLY, 750,000 cases of sepsis are reported in the United States, 1,2 and this disease is associated with a sustained high mortality rate, ranging from 15 to 50%. 3-9 Death relates to multiple organ dysfunction that involves kidneys, liver, pancreas, adrenals, coagulation system, central nervous system, cardiovascular system, and lungs. 10 Acute respiratory distress syndrome is a major remote organ pathology accompanied by sepsis. 11 Despite an increase in our knowledge of the pathogenesis of sepsis, all sepsis trials with immune-modulating drugs, most of which have targeted the sepsis-associated proinflammatory response, have reported no survival benefit. 12-14 One of the challenging issues for sepsis research is a heterogeneity of study populations; a vague definition of the disease accepts heterogeneity in microorganisms and the site of infection, 13 and genetic heterogeneity of hosts, which causes different responses to invading microorganisms. 15 Furthermore, immune status varies widely in the critically ill, usually preceding a hyperimmune state followed by subsequent immune paralysis, particularly in patients What We Already Know about This Topic • Sepsis is a leading cause of death, and targeting sepsisassociated inflammatory responses has not been shown to prove beneficial. What This Article Tells Us That Is New • In an established mouse model of sepsis (cecal ligation and perforation), severe versus mild sepsis was associated with increased mortality, less capacity of peritoneal inflammatory cells for phagocytosis, and decreased expression of focal and systemic cytokines and chemokine receptor expression on circulating neutrophils. These effects were reversed by the administration of the immune stimulant interferon-β after-but not before-severe sepsis was established. Interferon-β after the onset of peritonitis may restore impaired innate immunity and improve outcome.

No abstract