IntroductionMacrophages play a central role in antimicrobial immunity via their capacities for recognition, phagocytosis, and killing of opsonized and nonopsonized microbes. Nowhere are these functions more vigorously tested than in the lung, which comprises the largest internal interface with the outside environment and which is continuously exposed to microbes delivered via inhalation or oropharyngeal aspiration. 1 Particles opsonized by immunoglobulin (Ig)G antibodies bind to receptors recognizing the Fc portion of IgG (Fc␥ receptor [Fc␥R]). 2 There are 3 general classes of Fc␥R (Fc␥RI, II, and III) that vary in their molecular structure, affinity for different IgG isotypes, signal transduction, and phagocyte effector functions. 3 Not all Fc␥R classes are capable of eliciting phagocytosis. 3 In the human pulmonary alveolar macrophage (AM), Fc␥RI is the most abundantly expressed class of phagocytic Fc␥Rs, but low levels of Fc␥RIIa are also detected. 4 On Fc␥R clustering, its immunoreceptor tyrosine-based activation motif (ITAM) is phosphorylated by receptor-associated protein tyrosine kinases (PTKs) of the Src family (Src, Lck, Lyn, Fgr, Hck, Fyn, and Yes). The phosphorylated ITAM then serves as a docking site for Src-homology 2 domain-containing adapter proteins and enzymes, including Syk PTK, phospholipase C, the Ras-activating enzyme Sos, and phosphoinositide 3-kinase. 5 Upon their engagement by IgG-opsonized targets, both Fc␥Rs as well as some of their associated signaling molecules redistribute to lipid rafts (LRs), highly dynamic cholesterol-and sphingolipid-enriched microdomains that can act as platforms on which signaling proteins are assembled and which serve to compartmentalize a variety of cellular processes. 6 In addition to their roles in the membrane reorganization events of phagocytosis, these signaling molecules are also required for the induction of proinflammatory mediators involved in the amplification of phagocyte actions as well as the recruitment of leukocytes to the inflammatory milieu. 7 Among such mediators, the 5-lipoxygenase-derived products of arachidonic acid, leukotriene (LT) B 4 , and the cysteinyl LTs (CysLTs), LTC 4 , LTD 4 , and LTE 4 , enhance a myriad of leukocyte functions. 8 LTB 4 and CysLTs each bind 2 different classes of G protein-coupled receptors (GPCRs), termed leukotriene B 4 receptors 1 and 2 (BLT1 and BLT2) 9,10 and CysLT receptors 1 and 2 (CysLT1 and CysLT2). 11,12 GPCRs signal through the activation of small heterotrimeric G proteins that modulate the generation of second messengers, such as cyclic adenosine 5Ј-monophosphate and Ca 2ϩ . 13 We have shown that exogenously added or endogenously generated LTB 4 and LTD 4 promote Fc␥R-dependent phagocytosis and microbial killing in AMs via BLT1 and CysLT1, respectively; 14,15 however, there are key differences in the intracellular programs they use to enhance AM functions. First, LTB 4 / BLT1 is a more potent enhancer of AM phagocytosis and bacterial killing of IgG-opsonized targets than is LTD 4 /CysLT1. 16 Second,...