Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-γ- and CD40L-mediated costimulation

Abstract

Macrophages (Mphi) comprise a heterogeneous population of cells with various immune and homeostatic functions. Recently, we have described type-1 and type-2 human monocyte-derived Mphi subsets. Although both support outgrowth of intracellular mycobacteria, Mphi-1 secretes interleukin (IL)-23/IL-12 and supports T helper cell type 1 (Th1) responses, whereas Mphi-2 fails to produce IL-23/IL-12, predominantly secretes IL-10, and inhibits Th1 function. Here, we further describe the phenotypic and functional profiles of Mphi-1 and Mphi-2 in response to microbial antigens and interferon-gamma (IFN-gamma) and CD40L as costimulatory T cell back-talk signals. Activated IL-23(+)/IL-12(+) Mphi-1 secreted IL-1beta, IL-18, IL-6, and tumor necrosis factor-alpha (TNF-alpha), as well as IL-8, monocyte chemoattractant protein-1 (MCP-1), IFN-inducible protein 10 (IP-10), Mphi inflammatory protein-1beta (MIP-1beta), regulated on activation, normal T expressed and secreted (RANTES), Mphi-derived chemokine (MDC), and (low levels of) pulmonary and activation-regulated chemokine and thymus and activation-regulated chemokine (TARC), corroborating their proinflammatory function. Regardless of the stimulus, Mphi-2 maintained their IL-10(+) signature cytokine profile and produced no or relatively low levels of IL-12p40, IL-1beta, IL-6, TNF-alpha, MDC, or TARC. It is remarkable that Mphi-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1beta, and RANTES, suggesting an active role for these cells in regulating cellular immunity and homeostasis. Mphi-1 and Mphi-2 expressed similar levels of Toll-like receptor and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as microbial pattern recognition receptors. Mphi-2, unlike Mphi-1 but like other nonclassical Mphi described previously, expressed CD163 and down-modulated human leukocyte antigen and costimulatory molecules specifically upon activation. These findings demonstrate how Mphi-1/Mphi-2 polarization can differentially skew the host response toward pro- or anti-inflammatory immune responses, respectively. This is likely to be relevant for host-pathogen interactions in chronic bacterial infections and provides a model for dissecting pro- and anti-inflammatory cascades.

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…By contrast, the expression of markers related to M2 macrophage activation, such as CD16, CD163, MerTK, CD206, AMAC1 and CD200R1 [23][24][25][26][27], was upregulated in cmMTB-conditioned cells ( Figure 1B, Supplementary information, Figure S1B). Similarly, the expression of CCR2 and CCR5 chemokine receptors was higher in the presence of cmMTB, supporting the acquisition of the M2 program (Supplementary information, Figure S1C) [28,29]. More precisely, the expression of M2 markers was specifically augmented within CD16 + population compared with the CD16 − counterpart, with a higher increase of CD163 and CD206 upon cmMTB treatment monocytes ( Figure 1C).…”

“…Here we found that migration in Matrigel is mainly based on chemoattraction mediated by recombinant CCL5 but not CCL2 or CCL4 (Supplementary information, Figure S6E). Despite the fact that the expression of CCR2 and CCR5 was enhanced by cmMTB (Supplementary information, Figure S1C), and that their different chemokine ligands are strongly secreted by Mtb-infected macrophages [29,34], the depletion of CCL2, CCL4 and CCL5 from cmMTB did not significantly alter their migration properties (Supplementary information, Figure S6F). Since the activation program of macrophages modulates their 3D migration capacities [49], we hypothesized that the enhanced cell motility in response to cmMTB might result from the acquisition of the M2-like phenotype.…”

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

“…Of interest, this profile appeared to be more pronounced in patients with peripheral arthritis than in those with pure axial SpA (26). Based on the fact that IFN␥ is an important determinant of M1 polarization (2,3,(20)(21)(22) and on the association of synovial CD163ϩ M2 macrophages, but not T lymphocytes, with disease activity in peripheral SpA (9), the present study examined in more detail whether the presence of distinct macrophage subsets in both diseases is associated with different local inflammatory milieus.…”

“…M1 macrophages secrete large amounts of the key proinflammatory cytokines TNF␣ and IL-1␤ (20). Despite the similar degree of global joint inflammation, the SF levels of TNF␣ (mean Ϯ SEM 5.9 Ϯ 1.3 pg/ml versus 19.9 Ϯ 4.4 pg/ml; P ϭ 0.005) ( Figure 2D) and IL-1␤ (mean Ϯ SEM 3.2 Ϯ 1.0 pg/ml versus 24.1 Ϯ 5.3 pg/ml; P Ͻ 0.001) ( Figure 2E) were markedly lower in SpA than RA.…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…25 We further examined the expression of pattern recognition receptors involved in DV-induced inflammatory cytokine releases, such as Toll-like receptors (TLRs), [26][27][28] …”