Exploration for Promising Drug Targets Useful for the Development of Novel Antimycobacterial Agents Based on Macrophage Activation and Polarization

Mini Review

Austin J Clin Immunol. 2016; 3(1):1029.

Exploration for Promising Drug Targets Useful for the Development of Novel Antimycobacterial Agents Based on Macrophage Activation and Polarization

Haruaki Tomioka1,2*

¹Department of Basic Medical Science for Nursing, Yasuda Women’s University, Japan

²Faculty of Medicine, Shimane University School of Medicine, Japan

*Corresponding author: Haruaki Tomioka, Department of Basic Medical Science for Nursing, Faculty of Nursing, Yasuda Women’s University, Hiroshima 731- 0153, Japan

Received: November 15, 2015; Accepted: February 26, 2016; Published: April 11, 2016


The development of new antimycobacterial agents by focusing on unique drug targets related to bacterial virulence factors is urgently desired. For this purpose, mycobacterial proteins involved in interference with the host’s intracellular signalling events, which are required for the expression of antimicrobial functions of host macrophages (Mφs), are expected to serve as promising drug targets. From this viewpoint, the present review deals with the possible drug targets, especially those related to the M1- and M2-type polarization of host Mφs.

Keywords: Tuberculosis; Antimycobacterial Agents; Macrophage Polarization; Mycobacteria


Tuberculosis (TB), especially Multidrug-Resistant-TB (MDRTB), is a major global health concern since it is a highly contagious and life-threatening infection [1]. Moreover, intractable Mycobacterium avium Complex (MAC) infections, which are frequently encountered in AIDS patients, are currently increasing in the world [2]. Because of these serious situations, it is urgently necessary to develop new drugs exhibiting superior anti-M. tuberculosis (MTB) and/or anti-MAC activity by focusing on unique drug targets [3-5]. This can be achieved by logically designing novel antimycobacterial drugs which act on unique drug targets by clarifying the detailed properties of focused drug targets of pathogenic mycobacteria. It may be reasonable to design antimycobacterial compounds that are capable of blocking manifestation of the biological activity of bacterial virulence factors, especially those expressed during intramacrophage infection by pathogens. For this purpose, mycobacterial proteins involved in the bacterial interference of macrophage (Mφ) signaling pathways related to intramacrophage bacterial killing mechanisms may serve as favourable drug targets. Utilizing genomic and proteomic information on such virulence factors, it is possible to identify bacterial genes that encode potential target proteins useful for the development of new chemotherapeutics against mycobacteriosis. After elucidation of the detailed properties of such target proteins encoded by bacterial virulence genes, studies into practical drug design can be initiated by applying three-Dimensional Quantitative Structure Activity Relationship (3D-QSAR) analysis [6]. Notably, it is of marked interest to clarify the biochemical characteristics of bacterial proteins that crosstalk and interfere with the signal transduction cascades of host Mφs particularly those related to Mφ activation and polarization. This review article deals with the profiles of Mφ polarization induced by mycobacterial infection in host Mφs from the viewpoint of searching for unique drug targets for the development of new antimycobacterial therapeutics.

M1 and M2 Mφ polarization

Mφ polarization in bacterial infections, particularly those due to facultative intracellular pathogens including mycobacteria and Salmonella, is an important phenomenon for hosts [7,8]. Firstly, various bacteria induce the transcriptional activity of a common host response, which includes the expression of genes belonging to the M1 program, associated with Mφ polarization yielding the M1 Mφ population, which exerts proinflammatory and/or antimicrobial functions. In the activation of Mφs leading to M1 polarization, the NF-κB-mediated cascade plays a central role in intracellular signaling pathways in response to the stimulation of cell surface receptors for proinflammatory cytokines and Pathogen-Associated Molecular Pattern Molecules (PAMPs), such as IL-1β receptor, TNF-α receptor, and Toll-Like Receptors (TLRs) [9]. Secondly, since excessive or prolonged M1 polarization leads to tissue injury and contributes to the pathogenesis [10], the M2 Mφs with immunosuppressive and tissue-repairing functions play critical roles in the resolution of harmful inflammation via the production of anti-inflammatory mediators [7,8,10]. Indeed, in M2 Mφs, arginine metabolism is shifted to the production of ornithine and polyamines via arginase 1 [11-14]. However, some investigators argue against the classification, because these Mφs might be able to change from one phenotype to another, differing from the case of T cell subsets [11]. These investigators prefer to call M1 and M2 Mφs “classically activated Mφs” and “alternatively activated Mφs”, respectively. In this context, Murray et al. recently proposed a new nomenclature for these Mφ populations (activation standards), such as M(IL-4), M(Ig), M(IL-10), M(GC), M(IFN-γ), and M(LPS), indicating stimulation scenarios (the specific conditions for Mφ activation) [15].

M1 Mφs are induced to develop by the Th1-derived cytokine IFN-γ alone or in combination with other macrophage-activating cytokines (TNF-α and GM-CSF) and certain microbial stimuli such as LPS. In contrast to this, Th2-derived cytokines, IL-4 and IL-13, have been demonstrated to generate M2 Mφs [11,14]. M2 Mφs consist of four subpopulations: M2a Mφs (called “alternatively activated Mφs”) induced with IL-4 and IL-13; M2b Mφs (called “type II-activated Mφs”) induced with an immune complex and TLR/IL-1 receptor ligands via Fc receptors, complement receptors, and TLR; M2c Mφs generated in response to IL-10 and glucocorticoid hormones; and M2d Mφs characterized by an IL-10high, IL-12low M2 profile with some features of tumor-associated Mφs [6,7,12,16-20]. However, Murray’s proposal regards the M2a, M2b, M2c, M2d categories as inadequate, because they cause unnecessary complexity in understanding the modes of M2 polarization [15].

In general, M1 and M2 Mφ populations have distinct phenotypes because of differential profiles of gene expression as shown in Table 1 [21]. Firstly, typical M1 Mφs possess a phenotype with high-level production of IL-12 and IL-23 but low-level expression of IL-10. They are efficient producers of cytotoxic effector molecules, such as Reactive Oxygen Intermediates (ROIs) and Reactive Nitrogen Intermediates (RNIs) and inflammatory cytokines, including IL-1β, TNF-α, and IL- 6. Thus, M1 Mφs participate as inducer and effector cells in polarized Th1 responses and play roles in resistance against bacterial pathogens and tumors [11-13]. In contrast, the various forms of M2 Mφs share a phenotype with low-level production of IL-12 and IL-23 but highlevel expression of IL-10. In general, M2 Mφs, typically M2a Mφs, are characterized by low-level production of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6. However, M2b Mφs, which are characterized by high-level of IL-10 and CD86 expression, but lowlevel IL-12 and arginase 1 expression, are effective producers of IL-1β, TNF-α, and IL-6, as in the case of M1 Mφs [12,17,20,22]. In addition, M2b Mφs retain high level expression of inducible Nitric Oxide Synthase (iNOS) and RNI production [14,20]. Generally, M2 Mφs have high levels of mannose (typically M2a and M2c Mφs), scavenger (typically M2c Mφs), and galactose-type receptors. In addition, M1 Mφs and the various forms of M2 Mφs have distinct chemokine and chemokine receptor repertoires [23]. Notably, M2 Mφs principally play important roles in polarized Th2 reactions. For instance: (1) they promote the killing and encapsulation of parasites; (2) they promote tumor progression and tissue repair and remodeling; and (3) they have immunoregulatory and anti-inflammatory functions [11,24]. In addition, it has been reported that M2 Mφs inhibited the generation of M1 Mφs [24].

Citation: Tomioka H. Exploration for Promising Drug Targets Useful for the Development of Novel Antimycobacterial Agents Based on Macrophage Activation and Polarization. Austin J Clin Immunol. 2016; 3(1):1029. ISSN : 2381-9138