Some inflammatory diseases may become chronic due, at least in part, to a failure of events that normally bring about resolution of inflammation. We, and others, find evidence that atherosclerosis is characterized by failed resolution programs. However, in order to fully understand how inflammatory processes go awry in chronic diseases like atherosclerosis, it is imperative to understand the processes that bring about healthy resolution of acute inflammation. In general, neutrophils are largely cleared from sites of inflammation by local apoptosis. Monocyte-derived cells can also undergo local apoptosis, but the major mechanism mediating their clearance is thought to be emigration from the inflammatory focus to the draining lymph node through lymphatic vessels. This model for the fate of monocyte-derived cells during acute inflammation is, however, based on limited evidence, mainly derived from one study that tracked these phagocytes during the full course of acute inflammation. This and other related studies were carried out in the peritoneal cavity, a specialized anatomic compartment that can allow egress of macrophages to the omentum and other adjacent tissue in a nonspecific manner. Thus, in most other organs where more stringent requirements for migratory egress likely apply, removal of monocyte-derived cells from inflammatory sites may depend less upon emigration to lymph nodes, or only a subset of monocyte-derived cells may have the capacity to emigrate into lymphatic vessels. Indeed, no information is available on whether the two major subsets of monocytes are cleared from sites of inflammation by different mechanisms. Based on our past work and current preliminary data, we hypothesize that the emigration of monocyte-derived cells from sites of resolving inflammation requires development of a phenotype closely resembling Gr1lo monocytes, the """"""""nonclassical"""""""" CCR2loCX3CR1hi monocyte subset. We predict that Gr1lo monocyte-derived cells are readily cleared from sites of inflammation and indeed constitutively traffic first through tissue and then lymph continuously to give rise to a distinct population of CD11cint lymph node cells that may correspond to the dendritic cells historically termed """"""""lymph veiled cells."""""""" It is less clear whether Gr1hi monocyte-derived cells emigrate through lymphatics during resolution;we hypothesize that their migration through lymph requires conversion to a Gr1lo monocyte-derived cell phenotype and this conversion may depend upon appropriate signals at the site of inflammation. Here we will track the fate of monocyte subsets in models of acute inflammation that readily resolve (aim 1), analysis in steady state lymph (aim 2), and atherosclerosis, a model of failed resolution (aim 3).
Some chronic inflammatory diseases, like atherosclerosis, may perpetuate to their chronic state because signals that normally allow resolution of inflammation fail to be generated or perceived. In atherosclerosis, the recruitment and persistence of monocytes in the artery wall causes disease. Here, we will map the migratory behavior of monocyte-derived cell subsets to understand whether their ability to exit tissues through lymphatic vessels is a key behavior that maintains homeostasis in tissues and accounts for their removal during acute inflammatory responses, but which breaks down during progressive atherosclerosis.
|Ivanov, Stoyan; Scallan, Joshua P; Kim, Ki-Wook et al. (2016) CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J Clin Invest 126:1581-91|
|Kim, Ki-Wook; Williams, Jesse W; Wang, Ya-Ting et al. (2016) MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J Exp Med 213:1951-9|
|Durai, Vivek; Murphy, Kenneth M (2016) Functions of Murine Dendritic Cells. Immunity 45:719-736|
|Lu, Qun; Yokoyama, Christine C; Williams, Jesse W et al. (2016) Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. Cell Host Microbe 19:102-13|
|Wu, Xiaodi; BriseÃ±o, Carlos G; Durai, Vivek et al. (2016) Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells. J Exp Med 213:2553-2565|
|Mora-Bau, Gabriela; Platt, Andrew M; van Rooijen, Nico et al. (2015) Macrophages Subvert Adaptive Immunity to Urinary Tract Infection. PLoS Pathog 11:e1005044|
|Bagaitkar, Juhi; Pech, Nancy K; Ivanov, Stoyan et al. (2015) NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1Î±/G-CSF axis. Blood 126:2724-33|
|Kuan, Emma L; Ivanov, Stoyan; Bridenbaugh, Eric A et al. (2015) Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J Immunol 194:5200-10|
|Lavine, Kory J; Epelman, Slava; Uchida, Keita et al. (2014) Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci U S A 111:16029-34|
|Randolph, Gwendalyn J; Miller, Norman E (2014) Lymphatic transport of high-density lipoproteins and chylomicrons. J Clin Invest 124:929-35|
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