Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation

Abstract

The general paradigm is that monocytes are recruited to sites of inflammation and terminally-differentiate into macrophages. There has been no demonstration of proliferation of peripherally-derived inflammatory macrophages under physiological conditions. Here we show that proliferation of both bone marrow-derived inflammatory and tissue resident macrophage lineage branches is a key feature of the inflammatory process with major implications for the mechanisms underlying recovery from inflammation. Both macrophage lineage branches are dependent on M-CSF during inflammation, and thus the potential for therapeutic interventions is marked. Furthermore, these observations are independent of Th2 immunity. These studies indicate that the proliferation of distinct macrophage populations provides a general mechanism for macrophage expansion at key stages during inflammation, and separate control mechanisms are implicated.

Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System

“…However, unlike in other murine peritonitis models (17)(18)(19)(20) and also, for example, unlike in atherosclerotic lesions (62), local proliferation of AIP macrophages does not appear to be contributing to their increased numbers at least over the short 3-d period, but rather monocyte recruitment is the principal mechanism for the macrophage accumulation; their reduced numbers upon CSF-1 neutralization cannot therefore be due to suppressed proliferation in this model.…”

“…There has been more interest recently in the contribution of local proliferation of inflammatory macrophage/DC populations to their increased numbers (17,19,20,62). To explore whether reduced cell cycling in the inflamed cavity itself might be contributing to the lower numbers of AIP MPS populations observed earlier upon CSF neutralization, we pulse-labeled mAb-treated AIP mice with BrdU 2 h before termination at day 3.…”

“…A unified nomenclature has recently been proposed to attempt to circumvent this fundamental problem in which MPS cells can be classified primarily by their ontogeny and secondarily by their location, function, and phenotype in the steady-state and in inflammatory conditions (13). Even though a number of articles using sophisticated in vivo technology in mice have recently appeared addressing the origins of tissue macrophages during development, there is still debate around the fundamental question of the contribution, if any, of blood monocytes, including their subpopulations, to tissue macrophages in the adult at steady-state, and also to what extent local macrophage proliferation contributes to their homeostatic control or to that during inflammatory reactions (3,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

NBS1 is required for macrophage homeostasis and functional activity in mice

“…40 This is due to not only inflammatory macrophage recruitment but also to local macrophage proliferation that is M-CSF dependent. 41 We injected zymosan into the peritoneal cavity of both WT and Nbs1 ΔB/ΔB mice, and after 48 hours, we euthanized the mice and performed peritoneal lavages. The cells obtained were stained for CD11b, F4/80, and the intracellular proliferation marker Ki-67.…”

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

“…Certain tissue MF types (e.g., Kupffer cells, peritoneal, lung, splenic red pulp MFs, and microglia), are long-lived, reside in their specific tissue in a steady-state, and are not replenished by infiltrating monocytes (16). These MFs originate from different sources (e.g., the fetal liver and yolk sac) (17,18).…”