Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Abstract

Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBPbdependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4Ra) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBPb-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-Ra expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.Keywords: Arginase 1 . IL-4 . IL-10 . IL-4 receptor a . Visceral leishmaniasis IntroductionArginase is classically considered as a rate-limiting enzyme of the urea cycle in liver, but has been found to be present in a number of organs and tissues where the urea cycle is not operative. To date, two distinct isoforms of arginase have been identified in mammals. They are encoded by different genes differing in their cellular localization as well as their mode of regulation: type 1 arginase, a cytosolic enzyme expressed at high levels in liver, and type 2 arginase, a mitochondrial enzyme found in several tissues in addition to liver [1]. A growing body of evidence suggests that arginase induction is correlated with parasite-specific immunosuppression of host, thereby facilitating pathogen survival and growth inside the hostile environment of phagocytic cells. Macrophages were found to upregulate arginase 1 expression upon activation by Th2 cytokines and shown to have a detrimental role in parasite infection by limiting the Th1-dependent parasite clearance [2]. Interestingly, cAMP and TGFb are known to induce arginase 1 induction in macrophages [3]. In Chagas disease, induction of the arginase pathway could be used by Trypanosoma cruzi to spread inside host [4]. Arginase activity was triggered in macrophages from mice infected with the helminth Schistosoma mansoni and was associated with an increase in concentration of circulating L-ornithine-derived polyamines [5]. Intracellular pathogens like Salmonella enterica and Mycobacterium tuberculosis also utilize host arginase for their own 992survival within the macrophages [6,7]. Moreover, in bacteria like Helicobacter pyroli, arginase plays a major role in its surv...

Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

“…Third, as noted above, we found that at the site of visceral infection (spleen) in hamsters there is dominant expression of arg1, such that the arg1 to NOS2 ratio in hamsters with progressive disease was thousands-fold greater than the ratio observed in mice, which are able to control the infection. The non-induced arg1 mRNA expression in the L. donovani infected mouse spleen in our study was different from the 4.8-fold increase reported in a recent study [68]. This difference may be due in part to infection with a different L. donovani strain (Indian vs. East African) and use of a much larger inoculum in the study by Biswas, et al [68].…”

Growth Factor and Th2 Cytokine Signaling Pathways Converge at STAT6 to Promote Arginase Expression in Progressive Experimental Visceral Leishmaniasis

“…IL-10 appears to have a more limited role in that it upregulates arg1 mRNA, but not protein expression, in infected macrophages, and does not amplify the growth factor effect. Similarly, in L. donovani -infected mice, IL-10 does not directly induce macrophage arginase, but contributes indirectly to its expression by upregulating the type I IL-4 receptor [61]. FGF-2- and IGF-1 enhance expression of arg1 in L. donovani infected macrophages, but have a more modest effect on uninfected macrophages.…”

Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

“…STAT1 and STAT4 being transcription factors of IFNγ and IL-12 respectively are well correlated with enhanced IFNγ levels in mahanine-treated infected macrophages. In contrast, L. donovani induces STAT3 expression during infection, which is the inducer of a major immune suppressive cytokine (IL-10) 27 . Downregulation of p-STAT3 in mahanine-treated infected macrophages is further confirming the reversal of immunosuppressive condition confirming critical role of mahanine in the modulation of host’s cytokine response in clearance of the parasite.…”