The Long Pentraxin 3 (PTX3) Suppresses Immunity to Cutaneous Leishmaniasis by Negatively Regulating Th17 Response

Abstract

25 26 2 27 Abstract:28 The long Pentraxin 3 (PTX3), a soluble pattern recognition molecule, plays a critical role 29 in inflammation, tissue repair and wound healing. Here, we show that PTX3 regulates 30 disease pathogenesis in cutaneous leishmaniasis (CL). PTX3 expression is increased in 31 active skin lesions in patients and mice during CL, with higher levels being expressed in 32 individuals with severe disease. PTX3 deficient (PTX3 -/-) mice were highly resistant to L.33 major infection and the enhanced resistance was associated with increased IL-17 34 response. Neutralization of IL-17A abolished this enhanced resistance while treatment 35 with recombinant PTX3 resulted in reduced IL-17A response and increased susceptibility 36 to L. major infection. Naïve CD4 + T cells from PTX3 -/mice displayed increased 37 differentiation into Th17 cells, which was reversed in the presence of recombinant PTX3. 38 The enhanced Th17 response observed in PTX3 -/cells was associated with increased 39 Leishmania specific IL-6 production from dendritic cells along with enhanced expression 40 of Th17-specific transcription factors including RORt, AhR and STAT3. Addition of 41 recombinant PTX3 significantly inhibited the expression of Th17-specific transcription 42 factors and dramatically reduced the frequency of Th17 cells in Th17-polarizing cultures 43 of PTX3 -/-CD4 + T cells. Collectively, our results show that PTX3 contributes to the 44 pathogenesis of CL by suppressing Th17 differentiation and IL-17A production. 45 46 Author Summary:47 Cutaneous leishmaniasis (CL) is caused by several species of Leishmania. Currently, 48 there is no approved vaccine against human CL because of the poor understanding of 49 the mechanisms that regulate disease pathogenesis and correlates of protective 50 immunity. Because the long pentraxin 3 (PTX3, a soluble pattern recognition molecule 51 that forms an integral part of the host innate immunity), regulates inflammation and 3 52 tissue repair, which are critical physiological events associated with resolution of skin 53 lesions during CL, we investigated its role in disease pathogenesis.54 Here, we show that PTX3 levels were elevated in skin-lesions in patients and mice 55 during CL. Using a loss of function approach, we showed that PTX3 contributes to 56 pathogenesis, and this was associated with increased IL-17A responses. Neutralization 57 and recombinant cytokine treatment studies showed that the increased resistance of 58 PTX3 deficient mice to L. major is due to enhanced Th17 response in these mice. We 59 further show that PTX3 negatively regulates IL-6 production by dendritic cells and the 60 expression of IL-17A-specific transcription factors (including RORT, STAT3, IRF4, 61 BATF and AhR) in CD4 + T cells. Collectively, these findings show that PTX3 is a 62 negative regulator of Th17 response and protective immunity during L. major infection. 4 64 Introduction: 65 66 Cutaneous leishmaniasis (CL) is caused by several species of protozoan parasites that 67 belong to the genus Leishman...

Leishmania Immunity: Advancing Immunotherapy and Vaccine Development

“…The subsequent deletion of PTX-3 gene in the C57BL/6 mice resulted in enhanced resistance (reduced lesion size and parasite burden) following L. major infection. This was associated with significantly enhanced Th17/IL17 response, which we showed might be responsible for the enhanced resistance to L. major infection [125]. This study suggests that neutralization of PTX-3 in infected individuals may potentially reduce the severity of the disease.…”

“…Indeed, we found significantly higher levels of PTX-3 expression in skin biopsies of patients with active skin lesion caused by L. braziliensis infection. Treatment with chemotherapy significantly suppressed the expression of PTX-3 in these patients [125]. In another recent study, we showed that Semaphorin-3E (Sema3E), a host molecule involved in axon guidance, was increased at the site of L. major infection.…”