IL-4Rα-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice

PLoS One. 2015 Mar 19;10(3):e0121070. doi: 10.1371/journal.pone.0121070. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / biosynthesis
  • Arginase / metabolism
  • Bacterial Load*
  • Cell Proliferation
  • Disease Progression
  • Gene Expression Regulation, Enzymologic
  • Interleukin-4 Receptor alpha Subunit / immunology*
  • Macrophage Activation*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Mycobacterium tuberculosis / physiology*
  • Myeloid Differentiation Factor 88 / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Pulmonary Alveoli / immunology
  • Pulmonary Alveoli / microbiology
  • Survival Analysis
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / microbiology*
  • Tuberculosis, Pulmonary / pathology*

Substances

  • Interleukin-4 Receptor alpha Subunit
  • Myeloid Differentiation Factor 88
  • Nitric Oxide Synthase Type II
  • Arg1 protein, mouse
  • Arginase

Associated data

  • GEO/GSE56736

Grant support

This work was supported by the International Centre for Genetic Engineering & Biotechnology (ICGEB), Cape Town Component with Arturo Falaschi, Claude Leon Foundation and CIDRI, Wellcome trust (Grant No. 084323) post-doctoral fellowships to SPP. South African Medical Research Council (SAMRC) Unit on Immunology of Infectious Diseases (FB). A National Research Funding (NRF) South Africa and the South African Research Chair initiative (SARChi) to FB, the NRF Competitive Programme for Unrated Researchers (CSUR) and South African Medical Research Council (Self-Initiated Research Grant) to RG, the JST Strategic International Research Cooperative Program to HS and ICGEB Arturo Falaschi PhD Fellowship to MO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.