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Review
. 2014 Dec;26(6):471-85.
doi: 10.1016/j.smim.2014.09.010. Epub 2014 Oct 30.

Macrophage immunoregulatory pathways in tuberculosis

Murugesan V S Rajaram  1 , Bin Ni  1 , Claire E Dodd  2 , Larry S Schlesinger  3
Affiliations
Review

Macrophage immunoregulatory pathways in tuberculosis

Murugesan V S Rajaram et al. Semin Immunol. 2014 Dec.

Abstract

Macrophages, the major host cells harboring Mycobacterium tuberculosis (M.tb), are a heterogeneous cell type depending on their tissue of origin and host they are derived from. Significant discord in macrophage responses to M.tb exists due to differences in M.tb strains and the various types of macrophages used to study tuberculosis (TB). This review will summarize current concepts regarding macrophage responses to M.tb infection, while pointing out relevant differences in experimental outcomes due to the use of divergent model systems. A brief description of the lung environment is included since there is increasing evidence that the alveolar macrophage (AM) has immunoregulatory properties that can delay optimal protective host immune responses. In this context, this review focuses on selected macrophage immunoregulatory pattern recognition receptors (PRRs), cytokines, negative regulators of inflammation, lipid mediators and microRNAs (miRNAs).

Keywords: Innate immunity; Lung; Macrophages; MicroRNAs; Pattern recognition receptors.

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Figures

Figure 1
Figure 1. Depiction of the generation of AMs within the alveolar tissue environment
Blood monocytes traverse the pulmonary alveolar capillary bed and differentiate into intravascular macrophages in situ or transit to the interstitium to become interstitial macrophages (IMs), or to the alveolar space to become AMs (there is also evidence for local production of macrophages in mice). On route, the macrophages are “shaped” by locally produced determinants such as cytokines like GM-CSF, etc. Upon entering the alveolar space, AMs encounter surfactant components which play a role in differentiating these cells to their unique immunoregulatory phenotype, enabling them to acquire their primary function of enhancing clearance of particulates while limiting excessive pro-inflammatory “collateral” damage. Step 1 AM changes are immediate as a result of surfactant components, and other ligands, engaging their cognate receptors to generate a signaling cascade which alters the phenotype and function. Step 2 is long term resulting from an alteration in transcriptional programming. The unique AM phenotype requires constant input from the alveolar environment.
Figure 2
Figure 2. Schematic of macrophage activation by different stimuli that drive macrophage differentiation to different phenotypes
(a) Classically activated M1 macrophages are differentiated by IFN-γ, LPS and TNFα which lead to increased expression of pro-inflammatory mediators such as cytokines (TNFα, IL-1β, IL-12 and IL-6), iNOS, MHC-II molecule, and TLRs, as well as increased expression of FcγRs. (b) Alternatively activated M2 macrophages are differentiated by IL-4 and IL-13 which lead to an anti-inflammatory signature with increased expression of the MR (CD206), PPARγ, IL-10, CD200R, CD163, CD36, MARCO and SR-A. (c) AMs are unique immunoregulatory cells which express both M1 and M2 markers. Their activation is tightly regulated by molecules such as PPARγ, IRAK-M, IL-10 and SOCS proteins.
Figure 3
Figure 3. Schematic of macrophage regulatory factors that alter M.tb growth
(a) Activation of PRRs by M.tb and/or M.tb cell wall components, and downstream responses. TLR activation by M.tb cell wall components 38 kDa glycoprotein, LpqH, or PIMs promote inflammation; in contrast, LprA, LprG, PhoS1, LM and LAM increase the expression of anti-inflammatory mediators such as IL-10, IL-4 and TGF-β which enhance M.tb growth. MR-mediated phagocytosis of M.tb or MR stimulation by ManLAM delays P-L fusion and enhances PPARγ expression, leading to increased M.tb growth. TDM binding to Mincle or ManLAM to Dectin II enhance TNF1, IL-12 and IL-6 leading to granuloma formation and M.tb control. (b) Negative regulators of macrophage responses to M.tb and/or cell wall components. M.tb or ManLAM stimulation enhances the expression of various negative regulators, e.g. IRAK-M, SOCS-1 and SOCS-3, PPARγ, and TR4 as well as IL-10 and type I-IFNs which suppress host protective inflammatory mediators and promote M.tb growth. (c) Regulation of macrophage microRNAs and their functions in response to M.tb and/or cell wall components. miRNAs are important immune regulators during M.tb infection. Increased miR-125b targets TNFα for degradation, and miR-124 and miR-147 target TLR pathway genes such as MyD88 and TRAF6, are highly induced by M.tb infection and promote M.tb growth. (d) Impact of macrophage lipid mediators in response to M.tb and/or cell wall components. Lipid metabolites such as PGE2, LXA4 and LTB4 also regulate the macrophage immune response during M.tb infection. PGE2 and LXA4 are anti-inflammatory and promote M.tb growth. In contrast, LTB4 enhances bacterial killing during the early stage of infection and later promotes M.tb growth.
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