Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation.

Abstract

SummaryExpression of the macrophage mannose receptor is inhibited by interferon y (IFN-30, a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (I1:4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of Ib4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine Ib4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 12SI-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor ~ mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish II-4 as a potent and sdective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-% characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion. The macrophage mannose receptor (MMR) (previously called the mannosyl fucosyl receptor [MFR]) is an important phagocytic receptor mediating the binding and ingestion of micro-organisms with surface mannose residues and soluble mannose-containing glycoproteins. It is expressed on resident and elicited peritoneal macrophages and alveolar macrophages, not expressed on monocytes, and at low levels on Bacill~-Calmette-Guerin (BCG)-or IFN-3~-activated macrophages (1). Therefore, the MMR is a marker of the resident and elicited, but not IFN-y-activated, macrophage phenotype. MMR activity is increased by steroids and IFN-ol and -fl, and is inversely correlated with MHC class II antigen expression, which is induced on immunologically stimulated macrophages and used as a marker of activation. ID4, predominantly produced by activated Th cells of the type 2 phenotype and non-B, non-T, FcER + cells, has pleiotropic effects on a variety of immune and nonimmune cells. As it induces the expression of MHC class II antigen on B cells and monocytes, and enhances macrophage tumoricidal activity, it has been described as a macrophage-activating factor (2). However, the tumoricidal activity is confined to selected target cell lines, and only HLA-DR and HLA-DP but not HLA-DQ MHC class II molecules are induced by ID4. In addition, IL-4 induces MHC class II antigen expression on restricted macrophage populations. In contrast, IFN-3' induces all three class II molecules on most if not all macrophages (3, 4). Furthermore, Ib4 inhibits the expression of pro-inflammatory cytokine genes such as I1:1, TNF, and I1:8, and synergizes with steroids to inhibit macrophage proinflammatory activity (5-9). In addition, I1:4 inhibits superoxide anion release from PMA or zymosan-treat...

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…A particular feature of alternatively activated macrophages consisted in the abundance of several transcripts involved in cell cycle regulation. IL-4 has been shown to induce a marginal proliferative response in murine peritoneal macrophages [24], and alternatively activated macrophages modulate proliferation in co-cultured fibroblasts and endothelial cells [31,56]. It can thus be speculated that M. tuberculosis infection modifies cell cycle functions that form part of the program induced by IL-4.…”

“…Markers that have previously been used to identify human alternatively activated macrophages in vivo include a glucocorticoidinducible splice variant of the scavenger receptor CD163 [76] and the chemokine AMAC-1 [77], which is expressed by human alveolar macrophages and other cells [78]. The MMR has been used to identify murine alternatively activated macrophages [24]; however, since M. tuberculosis infection down-regulates surface expression of MMR, additional markers are required. Here, we identified MMP-12 as characteristic marker of alternative activation of macrophages, consistent with a functional involvement of alternatively activated macrophages and MMP in wound healing processes [79,80].…”

“…The macrophage mannose receptor (MMR) transcript was 7.6-fold more abundant in IL-4 macrophages. Since MMR is induced by IL-4 both on the transcriptional and functional levels [24,25] and since its cell surface expression is down-regulated by IFN-c [26], it has been used as a discriminative marker for alternatively activated macrophages [24,27]. In IL-4 macrophages, the high-affinity IgG receptor FccRI (CD64) was downregulated 9.4-fold.…”

Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

“…The macrophage MR has been associated with an anti-inflammatory phenotype in macrophages. 47, 48 The number of macrophages expressing MR at 5 days after IR with CSF-1 therapy was significantly increased than with vehicle-(P Ͻ 0.01) and sham-treated (P Ͻ 0.001) mice ( Figure 6A). These MR cells were also positive for F4/80 ( Figure 6A) with a shift from F4/80 ϩ MR hi population at 5 days after IR to a F4/80 ϩ MR lo population at 7 days after IR in response to CSF-1 ( Figure 6C).…”

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…M1 microglia and macrophages are triggered by factors including interferon (IFN)γ and TNF‐α and characterized by the release of reactive oxygen species (ROS) and inflammatory cytokines. Activation of microglia and macrophages by IL‐4, IL‐10, or tumor growth factor (TGF)β induces the M2 state, which is characterized by wound repair, debris clearance, and the release of anti‐inflammatory cytokines (Martinez & Gordon, 2014; Stein, Keshav, Harris, & Gordon, 1992). These opposing phenotypes play an important role in neuroinflammation and it is hypothesized that altering the activation of microglia and macrophages from the M1 side of the spectrum to the M2 side could be beneficial in ischemic stroke (Hu et al., 2012, 2015; Yenari, Kauppinen, & Swanson, 2010).…”