MicroRNAs (miRNAs) 3 are small (ϳ22-nucleotide) noncoding RNAs that regulate gene expression by binding to partially complementary sites in the 3Ј-untranslated regions (UTRs) of specific mRNAs, thereby promoting degradation and/or repressing translation of target mRNAs. The human genome contains Ͼ2500 unique mature miRNAs (1). Because individual miRNAs typically have multiple targets, it is thought that Ͼ60% of all human genes may be subject to regulation by miRNAs (2). The promiscuity of miRNAs for target RNAs is expected to represent a fundamental mechanism of cross-talk and coordination among signaling networks in development, health, and disease.Among the signaling networks that have been shown in recent years to be regulated by miRNAs are the Toll-like receptors (TLRs) of the innate immune system. Multiple TLRs up-regulate miRNAs, including miR-155, miR-146, miR-21, miR-147, and miR-9, whereas activation of TLR4 by lipopolysaccharide (LPS) down-regulates a distinct set of miRNAs (3, 4). In turn, miRNAs "fine tune" the proinflammatory signaling output of TLR cascades by controlling the expression of TLR pathway members (3, 4). Thus, miR-146 suppresses signaling by multiple TLRs via targeting the common signaling hubs IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 (5), whereas miR-155 has complex effects, repressing the TLR adaptor myeloid differentiation primary response 88 (MyD88) (6, 7) and TAK1-binding protein 2 (8), an upstream activator of the mitogen-activated protein kinases, but also promoting cytokine expression through actions on other targets (3). Although virtually all known examples of TLR regulation by miRNAs operate through direct targeting of TLR pathway components, it is expected that miRNAs may also indirectly impact the innate immune response by regulating other networks that cross-talk with TLRs.miR-33a and miR-33b (present in primates but absent in rodents and lower species in which miR-33a is simply referred to as "miR-33") are now known to be master regulators of cho-

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The neutrophil, a short-lived effector leukocyte of the innate immune system best known for its proteases and other degradative cargo, has unique, reciprocal physiological interactions with the lung. During health, large numbers of ‘marginated’ neutrophils reside within the pulmonary vasculature, where they patrol the endothelial surface for pathogens and complete their life cycle. Upon respiratory infection, rapid and sustained recruitment of neutrophils through the endothelial barrier, across the extravascular pulmonary interstitium, and again through the respiratory epithelium into the airspace lumen, is required for pathogen killing. Overexuberant neutrophil trafficking to the lung, however, causes bystander tissue injury and underlies several acute and chronic lung diseases. Due in part to the unique architecture of the lung’s capillary network, the neutrophil follows a microanatomic passage into the distal airspace unlike that observed in other end-organs that it infiltrates. Several of the regulatory mechanisms underlying the stepwise recruitment of circulating neutrophils to the infected lung have been defined over the past few decades; however, fundamental questions remain. In this article, we provide an updated review and perspective on emerging roles for the neutrophil in lung biology, on the molecular mechanisms that control the trafficking of neutrophils to the lung, and on past and ongoing efforts to design therapeutics to intervene upon pulmonary neutrophilia in lung disease.

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