IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

Abstract

Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. Keywords: IL-17 · IL-23 · Macrophage · Malaria · Plasmodium bergheiAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria, caused by protozoan parasites of the genus Plasmodium, is still one of the most life-threatening infectious diseases. Two hundred million people are infected annually with malaria paraCorrespondence: Dr. Hajime Hisaeda e-mail: hisa@med.gunma-u.ac.jp sites while about a million people are believed to die every year from the disease [1]. Despite the urgent need for effective vaccines against malaria, progress on vaccine development has been disappointing [2]. A major obstacle for vaccine development is that the immune responses crucial for eradication of malaria * These authors contributed equally to this work. parasites are not fully understood. Another concern is that infection with Plasmodium falciparum, which causes the most severe form of the disease in young children and pregnant women, can lead to pathological inflammation resulting in severe complications, such as cerebral malaria. Thus, to succeed in developing an effective vaccine against malaria, it is crucial that the mechanisms underlying protective immunity as well as those that drive pathogenic responses are better understood.IL-23 is a proinflammatory cytokine that belongs to IL-12 cytokine family. It is a heterodimeric molecule composed of p40 and p19 subunits [3]. The proinflammatory activities of IL-23 are responsible for the onset not only of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [4,5], but also infection-induced pathological consequences of infection with the pathogens causing Lyme disease and ...

Role of Dectin‐1 receptor on cytokine production by human monocytes challenged with Paracoccidioides brasiliensis

“…We also observed that monocytes were able to produce IL‐17A after the challenge with fungus, and this production was related to Dectin‐1, once the receptor blockage reduced the IL‐17A levels. GM‐CSF activation also led to an increase in IL‐17 production, in agreement with some studies showing the participation of phagocytic cells on IL‐17 production . Recently, it was demonstrated that the most severe form of PCM presents a response characterised by Th2/Th9 cells, whereas the milder and chronic inflammatory response presents a predominance of Th17 cells, with an important participation of Th1 cells .…”

“…GM-CSF activation also led to an increase in IL-17 production, in agreement with some studies showing the participation of phagocytic cells on IL-17 production. [71][72][73][74] Recently, it was demonstrated that the most severe form of PCM presents a response characterised by Th2/Th9 cells, whereas the milder and chronic inflammatory response presents a predominance of Th17 cells, with an important participation of Th1 cells. 75 Besides that, Loures et al 34 demonstrated that Th17 and Tc17 are expanded when induced by DC stimulated with P. brasiliensis due to the cooperation of TRL-4 with Dectin-1 and mannose receptors (MR).…”

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

“…SPMs are mobilized from blood monocytes, whereas LPMs are maintained independently of hematopoiesis (34). Importantly, IL-17 has previously been shown to recruit blood monocytes (46,47), as well as mature macrophages (48)(49)(50) to various tissues; and we have detected high levels of Il17ra selectively on SPMs isolated from ID8-bearing animals. Thus, our work identifies a link between IL-17-secreting γδ T cells and the mobilization/expansion of SPMs in the peritoneal cavity.…”

Cytokine profiles amongst Sudanese patients with visceral leishmaniasis and malaria co-infections

“…Interestingly, malaria appeared as the major trigger of this IL-17A up-regulation in co-infected patients, given that no relationship between patients’ demographic and clinical variables and the corresponding IL-17A serum level could be identified in this group (nor in any other group). Expansion of IL-17-producing cells (either CD4 +  T cells, CD8 + T cells or macrophages) and related cytokines (IL-17, IL-22 and IL-23) has been observed in P. vivax natural infections [59] as well as P. berghei , P. chabaudi and P. fragile animal models [60-62], where these interleukins have been shown to reduce parasite intensity and protect against fatal outcomes [59-61]. Conversely, a clear role of IL-17 immunity in P. falciparum infections is yet to be demonstrated.…”