Current concepts in granulomatous immune responses

Abstract

Persistent irritants that are resistant to innate and cognate immunity induce granulomas. These macrophage-dominated lesions that partially isolate the healthy tissue from the irritant and the irritant induced inflammation. Particles, toxins, autoantigens and infectious agents can induce granulomas. The corresponding lesions can be protective for the host but they can also cause damage and such damage has been associated with the pathology of more than a hundred human diseases. Recently, multiple molecular mechanisms underlying how normal macrophages transform into granuloma-inducing macrophages have been discovered and new information has been gathered, indicating how these lesions are initiated, spread and regulated. In this review, differences between the innate and cognate granuloma pathways are discussed by summarizing how the dendritic cell - T cell axis changes granulomatous immunity. Granuloma lesions are highly dynamic and depend on continuous cell replacement. This feature provides new therapeutic approaches to treat granulomatous diseases.

Keywords: VEGF; cell traffic; dendritic cells; granuloma.

Fig. 1. The complex role of granuloma DCs in the T cell pathway of granuloma formation

a) DCs reactivate antigen -specific T cells in acute granulomas, but tolerize them in chronic granulomas. b) DCs that present antigen, induce T cell priming but the migration of infected DCs contribute to the formation of new granulomas. Abbreviations: CCL, CC chemokine ligand; CD, cluster of differentiation; DC, dendritic cell; IFNγ, interferon gamma; MHCII, major histocompatibility complex II; PD-L, programmed death-ligand. Parts of the figure was adapted from (Schreiber et al. 2010; Harding et al. 2015a). Created with BioRender.com

Fig. 2. The production and role of VEGF-A and VEGF-C in granuloma formation and cellular traffic

a) Granuloma macrophages produce VEGF-A that promotes angiogenesis and recruits monocytes from the blood to the granuloma. b) Granuloma macrophages produce VEGF-C that promotes lymphangiogenesis, aiding DCs exit the granuloma. Abbreviations: eATP, extracellular adenosine triphosphate; HIF-1α, hypoxia-inducible factor 1-alpha; P2X7R, purinergic receptor P2X 7; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. Parts of the figure was adapted from (Harding et al. 2015b, 2019). Created with BioRender.com