TheIL‐13/IL‐4Rαaxis is involved in tuberculosis‐associated pathology

Abstract

Human tuberculosis (TB) is a leading global health threat and still constitutes a major medical challenge. However, mechanisms governing tissue pathology during post-primary TB remain elusive, partly because genetically or immunologically tractable animal models are lacking. In human TB, the demonstration of a large relative increase in interleukin (IL)-4 and IL-13 expression, which correlates with lung damage, indicates that a subversive T helper (TH)2 component in the response to Mycobacterium tuberculosis (Mtb) may undermine protective immunity and contribute to reactivation and tissue pathology. Up to now, there has been no clear evidence regarding whether IL-4/IL-13-IL-4 receptor-α (Rα)-mediated mechanisms may in fact cause reactivation and pathology. Unfortunately, the virtual absence of centrally necrotizing granulomas in experimental murine TB is associated with a poor induction of a TH2 immune response. We therefore hypothesize that, in mice, an increased production of IL-13 may lead to a pathology similar to human post-primary TB. In our study, aerosol Mtb infection of IL-13-over-expressing mice in fact resulted in pulmonary centrally necrotizing granulomas with multinucleated giant cells, a hypoxic rim and a perinecrotic collagen capsule, with an adjacent zone of lipid-rich, acid-fast bacilli-containing foamy macrophages, thus strongly resembling the pathology in human post-primary TB. Granuloma necrosis (GN) in Mtb-infected IL-13-over-expressing mice was associated with the induction of arginase-1-expressing macrophages. Indirect blockade of the endogenous arginase inhibitor l-hydroxyarginine in Mtb-infected wild-type mice resulted in a strong arginase expression and precipitated a similar pathology of GN. Together, we here introduce an experimental TB model that displays many features of centrally necrotizing granulomas in human post-primary TB and demonstrate that IL-13/IL-4Rα-dependent mechanisms leading to arginase-1 expression are involved in TB-associated tissue pathology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

“…Our findings agree with previous observations showing increased Arg1 mRNA expression and Arg1 activity over the course of aerosol Mtb infection and its association with augmented bacterial burden in murine lungs (22,26,50). Using the aerosol Mtb challenge of macrophage Arg1-deficient mice, El Kasmi et al (22) demonstrated improved control of Mtb in the lung.…”

“…Murine studies argue that Arg1 participates in dampening effective immunity against Mtb, because aerosol Mtb-infected mice that are deficient in macrophage-specific Arg1 have lower bacterial loads and smaller cellular infiltrates in the lungs than similarly infected WT mice (22). Moreover, Mtb aerosol infection of transgenic mice that overexpress IL-10 and IL-13 in macrophages results in increased pulmonary expression of Arg1, correlating with increased bacterial loads as compared with WT mice (25,26). In these mouse models, Arg1 expression was linked to reduced production of RNIs, suggesting that L-arginine depletion by Arg1 suppresses NOS2 activity and, therefore, Mtb killing (22,25).…”

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

“…Further, in IL-4 + IL-10-polarized MFs, the use of L-citrulline as a source of L-arginine may bypass arginase-mediated inhibition of iNOS function and elicit better antimycobacterial immunity. This method of polarization is likely relevant in vivo, because M. tuberculosis-infected patients with elevated type 2 cytokines have increased prevalence of TB (27)(28)(29). To test this, PDMs were stimulated with IL-4 + IL-10 for 24 h prior to infection to further induce Arg1 activity.…”

Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas

“…Caseous necrosis and cavitation during infection by M. tuberculosis is more prominent in rabbits and guinea pigs than in mice (2). Nevertheless, human-like pathology, as central granuloma necrosis and associated hypoxia, can be obtained in M. tuberculosis-infected I/StSnEgYCit, C3HeB/ FeJ, or IL-13-overexpressing C57BL/6 mouse strains (3)(4)(5). Confluent necrotic granulomas also are observed in mice deficient in gamma interferon (IFN-␥) or the type 1 tumor necrosis factor (TNF) receptor (2,6,7).…”