Resident Alveolar Macrophages Are Replaced by Recruited Monocytes in Response to Endotoxin-Induced Lung Inflammation

Abstract

In the acute respiratory distress syndrome, recruitment of peripheral blood monocytes results in expansion of the total pool of resident alveolar macrophages. The fate of resident macrophages, or whether recruited monocytes are selectively eliminated from the alveolar airspace or differentiate into resident alveolar macrophages during the resolving phase of inflammation, has not been determined. Here, we analyzed the kinetics of resident and recruited macrophage turnover within the alveolar airspace of untreated and LPS-challenged mice. Using bone marrow chimeric CD45.2 mice that were generated by lethal irradiation of CD45.2 alloantigen-expressing recipient mice and bone marrow transplantation from CD45.1 alloantigen-expressing donor mice, we employed a flow cytometric approach to distinguish recipient from donor-type macrophages in bronchoalveolar lavage fluids. Our data show that resident alveolar macrophages of untreated chimeric CD45.2 mice are very slowly replaced by constitutively immigrating CD45.1 positive monocytes, resulting in a replacement rate of approximately 40% by 1 yr. In contrast, more than 85% of the resident CD45.2 positive alveolar and lung homogenate macrophages were exchanged by donor CD45.1-expressing macrophages within 2 mo after treatment with Escherichia coli endotoxin (LPS). Importantly, fluorescence-activated cell sorter analysis of increased annexin V binding to both recipient and donor-type macrophages revealed increased apoptotic events to underlie this endotoxin-driven inflammatory macrophage turnover. Collectively, the data show that under baseline conditions the alveolar macrophage turnover exhibits very slow kinetics, whereas acute lung inflammation in response to treatment with LPS triggers a brisk acceleration of recruitment of monocytes that replace the resident alveolar macrophage population.

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

“…3A, Supplemental Fig. 1C) as previously reported (11). In nonirradiated C57BL/6 (i.e., CD45.2 allotype mice), all peripheral blood leukocytes were CD45.2 + (Supplemental Fig.…”

“…Shortly afterward, inflammatory blood monocytes (subpopulation M) are recruited into alveolar airspaces where they mediate bactericidal activity directly through phagocytosis and NO production, and indirectly through the amplification of the local inflammatory response. Although recruitment of inflammatory lung monocytes has been well studied (11,13,31), to our knowledge, we are the first to identify their simultaneous expression of both M1-and M2-like MF markers ex vivo. This is significant because the current doctrine tends to regard M1 and M2 MFs as differentially polarized MF subtypes that mediate distinct functions in the tissue microenvironment (32,33), trending the identification of a M2 MF based solely on its expression of M2 markers such as Arg I and IL-10.…”

“…There, they sit as a uniform, quiescent, and immunosuppressive population capable of pathogen phagocytosis and T cell recruitment in the early event of a bacterial or viral infection (9,10). Cell turnover rate is slow (11) and is maintained by constitutively immigrating CCR2 2 Gr-1 2 resident monocytes (12,13). In contrast, CCR2 + Gr-1 + inflammatory monocytes rapidly migrate into alveolar airspaces after lung infection and are believed to be the main effectors of acute lung injury and infection-related mortality (6,14,15).…”

Distinct Differentiation Potential of Blood Monocyte Subsets in the Lung

“…It was shown recently that endotoxin exposure accelerates replacement of pulmonary M⌽ by BM-derived cells as compared with noninflammatory conditions (39). In the DTx-induced cell ablation system, targeted cells die by apoptosis (24,40) and their replenishment might therefore mimic noninflammatory conditions.…”

Monocyte chemoattractant protein-1/CC chemokine ligand 2 enhances apoptotic cell removal by macrophages through Rac1 activation

“…High expression of MCP-1 in chronic diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and sarcoidosis [25,26,27] and the association between MCP-1-CCR2 and pathogenesis in bleomycin-induced mice pulmonary fibrosis has been reported [28]. The highly regulated kinetics of MCP-1 during acute inflammation In LPS-induced lung inflammation, resident alveolar macrophages are replaced by recruited alveolar macrophages in some proportion [30], and recruited alveolar macrophages have higher phagocytic activity than resident macrophages [24]. As discussed above, we used naïve resident alveolar macrophages.…”