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The IL ‐13/ IL‐4R α axis is involved in tuberculosis‐associated pathology
Author(s) -
Heitmann Lisa,
Abad Dar Mahin,
Schreiber Tanja,
Erdmann Hanna,
Behrends Jochen,
Mckenzie Andrew NJ,
Brombacher Frank,
Ehlers Stefan,
Hölscher Christoph
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4399
Subject(s) - immunology , granuloma , tuberculosis , immune system , biology , tumor necrosis factor alpha , pathology , giant cell , macrophage , mycobacterium tuberculosis , cytokine , medicine , biochemistry , in vitro
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 (R α )‐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‐4R α ‐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.