Macrophages are innate immune cells with well-established roles in the primary response to pathogens, but also in tissue homeostasis, coordination of the adaptive immune response, inflammation, resolution, and repair. These cells recognize danger signals through receptors capable of inducing specialized activation programs. The classically known macrophage activation is induced by IFN-gamma, which triggers a harsh proinflammatory response that is required to kill intracellular pathogens. Macrophages also undergo alternative activation by IL-4 and IL-13, which trigger a different phenotype that is important for the immune response to parasites. Here we review the cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures. We draw attention to discrepancies found between mouse and human models of alternative activation. The evidence for in vivo alternative activation of macrophages is also analyzed, with nematode infection as prototypic disease. Finally, we revisit the concept of macrophage activation in the context of the immune response.

Alternative Activation of Macrophages: An Immunologic Functional Perspective

Annexins are Ca2+ and phospholipid binding proteins forming an evolutionary conserved multigene family with members of the family being expressed throughout animal and plant kingdoms. Structurally,...

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Annexins: from structure to function.

https://pharmrev.aspetjournals.org/content/pharmrev/46/2/205.full.pdf

International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes.

https://science.sciencemag.org/content/sci/177/4053/949.full.pdf

Lectins: cell-agglutinating and sugar-specific proteins.

Lectins: Carbohydrate-Specific Proteins That Mediate Cellular Recognition.

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What should be called a lectin

We examined the cytolytic mechanisms of activated macrophages by using proteose peptone- or thioglycollate broth-induced mouse peritoneal macrophages or mouse macrophage hybridomas as effector cells, L.P3 cells, a clone of L929 cells, and P815 cells as target cells, and IFN-gamma and LPS as activators. It was determined that TNF is the main cytolytic molecule against L.P3 cells from the following results: 1) activated macrophages can produce TNF; 2) TNF shows cytotoxic activity against L.P3 cells; 3) the addition of anti-TNF antibody inhibited most of the cytolytic activity of activated macrophages against L.P3 cells. On the other hand, it was concluded that the main cytolytic mechanism against P815 cells is the production of NO2-/NO3- from L-arginine, from the following results: 1) activated macrophages can produce NO2-; 2) NaNO2 shows high cytotoxic activity against P815 cells; 3) the depletion of L-arginine from the medium inhibited most of the cytolytic activity of activated macrophages against P815 cells and NO2- production by activated macrophages. In this study, however, cytostatic effects of L-arginine-dependent effector mechanism were not studied. Thus, these results show that activated macrophages can express at least two cytolytic mechanisms independently, namely, the one that appears to be mediated by the L-arginine-dependent effector mechanism and the second that appears to be mediated directly by TNF. Furthermore, it was demonstrated that TNF and L-arginine-dependent NO2- production act synergistically as killing mechanisms of activated macrophages. These mechanisms can explain the cytolytic activity of activated macrophages against a variety of target cells.

Cytolytic mechanisms of activated macrophages. Tumor necrosis factor and L-arginine-dependent mechanisms act synergistically as the major cytolytic mechanisms of activated macrophages.

Purification and characterization of an anti-H(O) phytohemagglutinin of Ulex europeus

The structural requirements for the interaction of asparagine-linked oligosaccharide moieties of glycoproteins with wheat germ agglutinin (WGA) were investigated by using affinity chromatography on a WGA-Sepharose column. So-called hybrid-type glycopeptides obtained from ovalbumin [Yamashita, K., Tachibana, Y., & Kobata, A. (1978) J. Biol. Chem. 253, 3862--3869] were found to have high affinity for WGA--Sepharose, whereas high mannose-type and complex-type glycopeptides were shown to have low affinity. The elution profiles of various glycopeptides modified by glycosidase treatment, Smith periodate degradation, acetolysis, and hydrazinolysis showed that the GlcNAcbeta 1--4Manbeta 1--4GlcNAc beta 1--4GlcNAc-Asn structure was essential for the binding of glycopeptides to a WGA-Sepharose column. Thus, it was revealed that both the N,N'-diacetylchitobiose moiety and the beta-N-acetylglucosaminyl residue linked to C-4 of the beta-linked mannose residue contributed to the interaction of the glycopeptide with WGA-Sepharose. The substitution at C-6 of the innermost beta-N-acetylglucosaminyl residue by an alpha-fucosyl residue or at C-6 of the beta-linked mannose residue by another mannose residue in the above structure reduced the affinity of glycopeptides for the column.

Structural requirements for the binding of oligosaccharides and glycopeptides to immobilized wheat germ agglutinin

A human macrophage calcium-dependent (C-type) lectin cDNA clone was obtained from a library derived from IL-2-treated peripheral blood monocytes. The cDNA cloning was based on the structural homology to hepatic asialoglycoprotein receptors. The nucleotide sequence of this cDNA clone was homologous to those of the galactose- and N-acetylgalactosamine-specific C-type macrophage lectins of rodents. In the putative carbohydrate recognition domain, deduced amino acid sequence revealed 60 and 63% homology to galactose- and N-acetylgalactosamine-specific C-type macrophage lectins of mice and rats, respectively. The cDNA clone was ligated into a mammalian expression vector and transfected into COS-1 cells. In the lysates of these cells, an MR 38,000 component, which bound to galactose-Sepharose, was identified after electrophoretic separation by its interaction with polyclonal antisera against synthetic polypeptides representing a portion of the carbohydrate recognition domain. The carbohydrate-binding specificity of the recombinant macrophage lectin was investigated by comparing elution profiles of various glycopeptides having defined carbohydrate structures from immobilized macrophage lectins. When N-terminal octapeptides from human glycophorin A that bore NeuAc alpha 2-3 Gal beta 1-3 (NeuAc alpha 2-6) GalNAc and its sequentially deglycosylated derivatives were compared, glycopeptides carrying three constitutive GalNAc-Ser/Thr (Tn Ag) strongly bound to the recombinant human macrophage lectin. This is the first study to demonstrate that human macrophage cell surface lectin recognizes Tn Ag, a well-known human carcinoma-associated epitope.

Toshiaki Osawa

Papers

What should be called a lectin

Cytolytic mechanisms of activated macrophages. Tumor necrosis factor and L-arginine-dependent mechanisms act synergistically as the major cytolytic mechanisms of activated macrophages.

Purification and characterization of an anti-H(O) phytohemagglutinin of Ulex europeus

Structural requirements for the binding of oligosaccharides and glycopeptides to immobilized wheat germ agglutinin

Molecular cloning and expression of cDNA encoding human macrophage C-type lectin. Its unique carbohydrate binding specificity for Tn antigen.