Alveolar macrophage deficiency in osteopetrotic mice deficient in macrophage colony-stimulating factor is spontaneously corrected with age and associated with matrix metalloproteinase expression and emphysema

Abstract

IntroductionAlveolar macrophages (AMs) are pulmonary residents of the bone marrow-derived mononuclear phagocyte system that play a critical role in several diverse lung functions and in lung host defense. 1 AMs arise from circulating blood monocytes that enter the lungs and other tissues 2,3 and undergo terminal differentiation into tissue macrophage populations that are heterogeneous in their level of accumulation, 4,5 functional activity, 4 and expression of cell-surface molecules. 6,7 The mechanisms regulating the abundance and heterogeneity of AMs and other tissue macrophage populations are not well defined. However, exposure of macrophages to different tissue microenvironments varying in the local amount or form of hematologic growth factors capable of regulating macrophage proliferation has been proposed. 5 Macrophage colony-stimulating factor (M-CSF, also known as CSF-1) is one of several factors known to regulate the survival, proliferation, and differentiation of mononuclear phagocytic lineage cells. 8 M-CSF is abundant in blood, present in most tissues (though in lower and various levels depending on the type of tissue), and expressed as 3 biologically active forms: a circulating secreted glycoprotein isoform, a proteoglycan isoform, and a cell-surface isoform produced locally in tissues. 8,9 Recombinant M-CSF was shown to promote accumulation of murine AMs in vivo 10 and survival of human AMs in vitro, 11 and M-CSF levels are increased in the lungs of smokers in association with significant increases in numbers of AMs. 12 Granulocyte-macrophage colonystimulating factor (GM-CSF) and interleukin 3 (IL-3) are also capable of regulating macrophage proliferation. 5,13 AM numbers are increased markedly in transgenic mice expressing GM-CSF in the lung from a lung-specific transgene. 14 However, AM numbers are not reduced in GM-CSF knockout mice lacking GM-CSF, 15,16 suggesting that GM-CSF is not essential for constitutive accumulation of AMs.Osteopetrotic mice are homozygous for a naturally occurring recessive frameshift mutation (Csf-1 op or Op) in the M-CSF gene 17 and consequently have no M-CSF. 18 They thus provide a good model for studying the role of M-CSF in vivo. In Op/Op mice, various M-CSF-dependent macrophage populations are decreased in number and show developmental anomalies in a tissue-specific manner. 5,19,20 For example, bone marrow monocytes/macrophages, which usually increase progressively with age in normal mice, are reduced in number in young Op/Op mice. 5 However, bone marrow macrophages still increase in number with age in these mice in parallel with spontaneous correction of osteopetrosis. 21 Macrophage populations that increase transiently in number at 2 weeks of age in normal mice are reduced in number, with or without preservation of the transient increase (eg, in the intestine or The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C....

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

“…Interestingly, high MMP-12 expression tracks specifically with the Mac-1 pos AMF subpopulation in C57BL/6 SHIP-1 2/2 mice. Downstream MMP-12 upregulation is a common feature of all COPD animal models (7,17,41,42), implicating its role as a major COPD effector. Clinically, a minor SNP allele in MMP-12 that reduces its protease activity is protective against COPD onset in smokers (43).…”

“…Although large vacuolated AMFs are found in almost all animal models of COPD (7,17,41,42), no single pathological AMF subpopulation has yet been identified or associated with disease pathogenesis. In this article, we report the presence of a subpopulation of constitutively Mac-1 pos residential AMFs in C57BL/6 SHIP-1 2/2 mice that spontaneously develop COPD-like lung disease.…”

“…Increased AMFs, however, are correlated with the severity of chronic obstructive pulmonary disease (COPD) (16), a debilitating chronic condition characterized by progressive irreversible airflow limitation and lung parenchyma destruction. Altered AMF behavior is also observed in animal models of COPD, chronic lung inflammation, and tumorigenesis (7,8,17,18), making the behavior of lung MFs an important field of study.…”

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

“…Both MMP-2 and MMP-9 are capable of elastolysis as well as collagenolysis (33), while MMP-12 is elevated in mice exposed to cigarette smoke and MMP-12 KO mice are protected from cigarette smoke-induced emphysema (30), and alveolar macrophages release more MMP-9 in chronic obstructive pulmonary disease patients and cigarette smokers (34,35). Osteopetrotic mice, deficient in macrophage CSF, develop emphysema and have higher levels of MMP-2, MMP-9, and MMP-12 in BAL fluid and alveolar macrophages than in controls (36), while lung surfactant protein D gene-inactivated mice have airspace enlargement associated with an increase in the same three MMPs (37). Finally, the balance of MMPs to TIMPs within the local tissue microenvironment is important in the process of emphysema, as indicated in TIMP-3 KO mice, which develop progressive airspace enlargement (38).…”

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

“…CSF1 op /CSF1 op mice, which produce an aberrant form of M-CSF, exhibit a severely reduced cellularity in the BM, a reduced number of circulating monocytes and deficiency in some tissue macrophage populations (2)(3)(4)(5). However, follow-up studies showed that there is no reduction in circulating monocytes, and the selective deficiency in tissue macrophage populations is corrected as CSF1 op /CSF1 op mice age (6,7). Because of the conflicting results, whether M-CSF functions in monocyte production in the BM or at the transition of monocyte into macrophage in the tissues is still controversial (3,4,6,(8)(9)(10).…”