Macrophage biology and immunology: man is not a mouse

Abstract

A recent article by Shibata et al. [1] and an interview with the senior investigator Kobayashi [2], both in the October 2006 issue of Journal of Leukocyte Biology, discuss the role of macrophage-derived NO in the clearance of apoptotic cells. We were surprised that neither in the original paper nor in the accompanying interview was it discussed that these results rely entirely on data obtained in murine macrophages. It is, however, evident that there are differences in macrophage NO production and regulation among different species [3,4]. Several years ago, we and others [5][6][7] described fundamental differences between macrophages from mice and humans regarding NO synthase (NOS) activity. Murine macrophages produce large amounts of NO and L-citrulline from L-arginine via induction of the inducible form of NOS (iNOS). In parallel, murine macrophages synthesize the obligatory cofactor tetrahydrobiopterin (BH4), essential for stabilization and function of the iNOS enzyme protein [8,9]. Human as well as macrophages from other animal species, such as rabbits, goats, or Syrian hamsters, do not have NOS activity nor do they synthesize BH4 [7,10,11]. In addition, murine macrophages consume most of the L-arginine by another enzyme-arginase-and convert it into L-ornithine. This arginase is not active in human macrophages too [7,9,12]. A lot of research has since been done to demonstrate nitrite production in human macrophages. Recent reviews claim that human macrophages have iNOS activity, albeit induced by other stimuli rather than those inducing nitrite production in murine macrophages [13]. We evaluated several of these stimuli and could show that nitrite was not produced by iNOS activity in human macrophages. The nitrite measured came from other noncellular sources [14]. None of the articles cited as proof for iNOS activity in human macrophages provides sound biochemical data about L-arginine consumption, BH4 synthesis, and L-citrulline production [13]. Moreover, they do not control for nitrite generation from other nonmacrophage sources [14]. The only report that demonstrates nitrite production from NOS activity in human macrophage-like cells is an article by Bertholet et al. [15]. There, the U937 monoblastic leukemia cell line was transfected with a plasmid containing a functional iNOS gene. Nitrite production by these cells, however, totally depended on substitution of the cofactor BH4 and additional substrate [15]. As species differences are not confined to NOS activity and are fundamental in many aspects of immunology [3,16,17], we propose that the species involved should be mentioned in the title and abstract of articles dealing with common aspects of immunity.

Pig Bone Marrow-Derived Macrophages Resemble Human Macrophages in Their Response to Bacterial Lipopolysaccharide

“…All three species induce the enzyme GCH1, which generates the cofactor tetrahydrobiopterin (BH4), and the by-product neopterin, which is a common marker of inflammation (64). Like human macrophages, and in keeping with earlier findings on other pig macrophage populations, pig BMDM did not produce NO, nor did they induce arginine-metabolizing genes or CAT2 in response to LPS (44,45). In addition, the response of pig macrophages was unaffected by preincubation with CSF-1 in common with human, and quite distinct from mouse macrophages (58).…”

“…As noted in the introduction, mouse macrophages respond to LPS with induction of arginine metabolism, inducible NO syn- thase, and production of NO, whereas human macrophages do not (44,45). One difficulty in comparisons of mouse and human has been that comparisons are made between monocytes-macrophages from different locations or differentiation states.…”

Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages

“…Moreover, discrepancies between mice and human macrophages are well documented, especially concerning iNOS and arginase-1 expression. 15,40 The present results suggest that ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated pathologies through their production of the proatherogenic MMP-9. Furthermore, the ATM-mediated antiadipogenic effect may contribute to lipotoxicity by promoting the ectopic deposition of free fatty acids in non-ATs.…”

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

“…For example, the nucleotide binding domain-leucine-rich repeat region of NLRP3 differs from Nlrp3 in the distribution of potential serine/threonine phosphorylation sites, oxidant-sensitive cysteine residues, charged residues, and lysines that may serve as ubiquitination sites (data not shown). However, our results cannot rule in a critical function difference based on amino acid sequence, thus both the possible contribution of specific residues and potential differences acting in an indirect fashion such as species differences in reactive oxygen generation (53,57). Sensitivity to apoptotic/pyroptotic death signals and potential ligand adapter proteins (58) should be considered.…”