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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049653-14
Application #
8422970
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Peyman, John A
Project Start
2011-09-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
14
Fiscal Year
2013
Total Cost
$282,902
Indirect Cost
$96,782
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Randolph, Gwendalyn J; Miller, Norman E (2014) Lymphatic transport of high-density lipoproteins and chylomicrons. J Clin Invest 124:929-35
Nascimento, Marcia; Huang, Stanley C; Smith, Amber et al. (2014) Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis. PLoS Pathog 10:e1004282
Gautier, Emmanuel L; Ivanov, Stoyan; Williams, Jesse W et al. (2014) Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J Exp Med 211:1525-31
Randolph, Gwendalyn J (2014) Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res 114:1757-71
Gautier, Emmanuel L; Ivanov, Stoyan; Lesnik, Philippe et al. (2013) Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Blood 122:2714-22
Platt, Andrew M; Rutkowski, Joseph M; Martel, Catherine et al. (2013) Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia. J Immunol 190:4608-20
Jakubzick, Claudia; Gautier, Emmanuel L; Gibbings, Sophie L et al. (2013) Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39:599-610
Potteaux, Stephane; Gautier, Emmanuel L; Hutchison, Susan B et al. (2011) Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest 121:2025-36
Monrad, S U; Kojima, F; Kapoor, M et al. (2011) Genetic deletion of mPGES-1 abolishes PGE2 production in murine dendritic cells and alters the cytokine profile, but does not affect maturation or migration. Prostaglandins Leukot Essent Fatty Acids 84:113-21
Desch, A Nicole; Randolph, Gwendalyn J; Murphy, Kenneth et al. (2011) CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J Exp Med 208:1789-97

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