Educating the Innate Immune System

Circulating granulocytes are maintained within a fairly narrow window for each individual during homeostasis. This regulatory system is nonetheless capable of dramatic shifts during stress. The mechanisms that govern control over granulocyte number remain incompletely understood. Recent information, however, provides clues to the feedback control systems that regulate homeostatic and emergency granulopoiesis. The first clues have come from adult mice with abnormalities in granulocyte function. Defects in Leukocyte Integrins or chemokine receptors result in marked increases in circulating (?2 integrin) or bone marrow (Cxcr2) neutrophils, associated with increased circulating IL-17 and G-CSF. This result appears to be due to a functional inability to arrive at sentinel site(s) whence they are attracted by (among others) Cxcl5. Strikingly, a single infusion of normal WT neutrophils resets this feedback loop. One signal for expression of IL-17 and G-CSF appears to be the gut microbiome. Antibiotic treatment also resets the system, reducing neutrophil numbers and cytokine expression. Thus, at sentinel site(s), the supply of functional neutrophils is balanced against perceived threat from the microbiome. In neonates, exposure to commensal organisms is an immediate result of birth from a sterile environment into a dirty one. We have described postnatal granulopoiesis in murine neonates, a dramatic increase in circulating and bone marrow neutrophils, that lasts for 5-7 days. Human infants similarly have been shown to demonstrate a postnatal increase in circulating neutrophils for 72 hrs after birth. Antibiotic-exposed mouse pups fail to develop postnatal granulopoiesis, as do mice deficient in IL17ra, MyD88, TLR4, or G-CSF even if not exposed to antibiotics, indicating a pathway that requires exposure to LPS that induces IL17 and G-CSF, as in adults. In contrast to adults, however, commensal bacteria are required for host defense. Antibiotic-exposed pups are exquisitely sensitive to E. coli sepsis, which can be partially reversed by transfer of cecal contents or exogenous G-CSF. Furthermore, small quantities of LPS, fed by gavage, can also partially protect. Thus, neonates use exposure to commensal bacteria and their products to trigger the rapid expansion and functional maturation of granulocyte development, and in so doing, prepare the neonate for potential exposure to pathogens. Adults maintain this system, where it is at least partially responsible for maintenance of granulocyte homeostasis.