Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-β

Abstract

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.

Interleukin‐38 protects against sepsis by augmenting immunosuppressive activity of CD4+CD25+ regulatory T cells

“…[17][18][19][20][21][22][23][24] It is well known that Tregs play a critical role in regulating immune homeostasis, including several pathological conditions such as allergic lung inflammation, autoimmune diseases, transplant rejection and tolerance. [17][18][19][20][21][22][23][24] It is well known that Tregs play a critical role in regulating immune homeostasis, including several pathological conditions such as allergic lung inflammation, autoimmune diseases, transplant rejection and tolerance.…”

“…Previous work revealed that LPS could activate CD4 + CD25 + Tregs via TLR4 signalling. [19][20][21][22] Sepsis is typically characterized by initial hyper-inflammatory Th1 response, which is associated with disease severity and mortality. As we known, Tregs use different pathways to limit inflammatory and immune responses.…”

“…There is no specific pharmacotherapy for septic patients, although manipulation of immune response may be a promising strategy for an effective treatment. [17][18][19][20][21][22][23][24] It is well known that Tregs play a criti- following stimulation with rhinovirus, inflammatory cytokines, F I G U R E 8 Impact of CD4 + CD25 + Treg depletion on IL-38-mediated protection against sepsis CD4 + CD25 + Tregs was isolated from murine splenocytes. (A, B) Flow cytometry plots showed CD4 + CD25 + Tregs in the spleen at 48 h after treatment with anti-CD25 antibody (PC61) (n = 6 per group).…”

Post-surgical immune suppression: another target to improve postoperative outcomes

“…Restoring macrophage function with cytokines such as interferon (IFN)-β improved survival [17]. Furthermore, the functional decline of peritoneal macrophages occurred within 24 h after the onset of peritonitis and was restored by the systemic administration of IFN-β [18]. Therefore, some septic patients may benefit from early immune-enhancing therapy.…”

“…For patients undergoing surgery, given that the high surgical insult may lead to the situation similar to infection-induced sepsis, it is thought that early immune-enhancement may also be effective. However, our mouse model showed that the prophylactic administration of IFN-β had a worse outcome for peritoneal sepsis [18].…”