Th1-Th2 Cross-Regulation Controls Early Leishmania Infection in the Skin by Modulating the Size of the Permissive Monocytic Host Cell Reservoir

Abstract

Highlights d Th1-Th2 cross-regulation impacts early Leishmania skin infection via monocyte recruitment d STAT6 reduces monocyte recruitment via IFN-g but controls phagocyte activation via IL-10 d Infected monocytes attain an alternatively activated PDL2+phenotype in a Th1 environment d Th2 immunity does not facilitate pathogen replication on a per cell basis

Immunometabolism of Leishmania granulomas

“…19,46 By contrast, conditional knockdown of Arg1 expression or a block in Arg1 induction in C57BL mice that form selfcuring lesions had no effect on the progression of disease or parasite persistence after granuloma resolution. 9,44 Moreover, proliferating L. major parasites did not exhibit a tropism for Arg1 + macrophages in latent C57BL infections, indicating that elevated expression of host arginase is not essential for intracellular survival. 47 These differences in the significance of host arginase in Leishmania infection outcomes likely reflect variability in Arg1 expression in different mouse strains (normally much higher in BALB/c mice) and in the innate microbicidal capabilities of BALB/c and C57BL mice.…”

“…Arg1 is reciprocally regulated with iNOS at the level of transcription (although Arg1 + /iNOS + macrophages are detected in lesions) as well as metabolically. 9 Specifically, upregulation of Arg1 diverts arginine from NO production, while upregulation of iNOS results in the generation of N x -hydroxy-L-arginine, a potent inhibitor of arginase. As a result, elevated expression of Arg1 in myeloid cells limits the antileishmanial effector functions, as well as the inflammatory effects of iNOS/NO.…”

“…Arg1 catalyzes the conversion of arginine to ornithine and urea, thereby promoting de novo glutamine, proline and polyamine synthesis which sustains collagen production and the tissue repair functions of M2 macrophages. Arg1 is reciprocally regulated with iNOS at the level of transcription (although Arg1 + /iNOS + macrophages are detected in lesions) as well as metabolically 9 . Specifically, upregulation of Arg1 diverts arginine from NO production, while upregulation of iNOS results in the generation of N ω ‐hydroxy‐ l ‐arginine, a potent inhibitor of arginase.…”

“…Further recruitment of monocytes and other immune cells leads to the development of granulomatous lesions in the skin composed of infected and uninfected macrophages, monocytes and dendritic cells, as well as a significant number of neutrophils (that can also be infected) and eosinophils 6–8 (Figure 1a). Expansion of the granuloma occurs through the interferon‐γ (IFNγ)‐mediated recruitment of inflammatory monocytes that rapidly outnumber tissue macrophages and actively phagocytose dying infected host cells, promoting parasite transmission between monocytes and macrophages in the lesions 9–11 (Figure 1a). These primary lesions are major sites of parasite expansion or control, as well as a source of parasites that seed secondary granulomas in other dermal sites or internal organs in susceptible hosts.…”

Acute IL-4 Governs Pathogenic T Cell Responses duringLeishmania majorInfection

“…Altogether, these studies demonstrate a critical protective role for IFN-γ–producing Th1 CD4 + T cells during L. major infection. Interestingly, more recent work by Carneiro et al ( 15 ) suggests that early IFN-γ production is required for recruitment of parasite-permissive monocytes, suggesting early Th2 responses that cross-regulate Th1 responses (i.e., IFN-γ) may be beneficial for the host.…”