Abstract
Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild-type (WT) and LysMcreIL-4Rα-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb-infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow-derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Rα driven pathway. Together, these results suggest that IL-4Rα-macrophages do not play a central role in TB disease progression.
Highlights
Classical activation of macrophages results in concomitant production of reactive nitrogen intermediates (RNIs) such as nitric oxide (NO), killing intracellular Mycobacterium tuberculosis (Mtb) [1]
Specific depletion of Arginase 1 (Arg1) in macrophages using the CreLoxP recombination system resulted in elevated NO levels that contributed to 1-log reduction in lung colony counts following Mtb H37Rv infection [17]
Deleting the IL-4Rα signalling pathway would lead to increased availability of L-Arginine substrate for inducible nitric oxide synthase (iNOS), leading to enhanced NO-mediated killing functions
Summary
Classical activation of macrophages results in concomitant production of reactive nitrogen intermediates (RNIs) such as nitric oxide (NO), killing intracellular Mtb [1]. Arg was induced in HN878-infected murine macrophages [13] and is expressed in lung granulomas of TB patients [14] suggesting possible avoidance of NO mediated killing by the hypervirulent strain of Mtb. The induction of Arg by TH2 cytokines in macrophages is well studied and requires STAT6 signalling through the IL-4Rα chain [2, 15, 16]. Two in vitro studies showed that M. bovis BCG induces Arg through a MyD88-dependent pathway but in an STAT6independent manner [13, 17]. Qualls et al characterized the pathway involved and revealed that M. bovis BCG-infected macrophages secrete MyD88-dependent IL-6, IL-10 and G-CSF that induces Arg expression in an autocrine/paracrine manner [13]. This suggests that IL-4Rα-activated macrophages are not required for TB disease progression since Mtb induces Arg production independent of the IL-4Rα signalling pathway
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